Oxysterols and methods of use thereof

Abstract

To provide compounds useful for the prevention and treatment of a variety of conditions.SOLUTION: Provided herein are compounds according to formula (I) and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; in the formula R1, R2 and R5 are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions. Provided herein are substituted oxysterols useful for preventing and / or treating a broad range of disorders, including, but not limited to, NMDA-mediated disorders. These compounds are expected to show improved in vivo potency, pharmacokinetic (PK) properties, oral bioavailability, formulation suitability, stability and / or safety compared to other oxysterols. Further provided are pharmaceutical compositions comprising the compounds of the present invention, and methods of their use and treatment.SELECTED DRAWING: None

Description

[Technical field]

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 62 / 189,068, filed July 6, 2015, and U.S. Provisional Application No. 62 / 332,931, filed May 6, 2016, the contents of each of which are incorporated by reference in their entirety herein. [Background technology]

[0002] 2. Background of the Invention NMDA receptors are heteromeric complexes containing NR1, NR2 and / or NR3 subunits, and have distinct recognition sites for exogenous and endogenous ligands. These recognition sites include binding sites for glycine and binding sites for glutamate agonists and modulators. NMDA receptors are expressed in peripheral tissues and the CNS, where they are involved in excitatory synaptic transmission. Activation of these receptors contributes to synaptic plasticity in some situations and excitotoxicity in others. These receptors are ligand-gated ion channels that accept Ca2+ after binding of glutamate and glycine, and are essential for excitatory neurotransmission and normal CNS function. Positive regulators may be useful as nootropics and as therapeutic agents with potential clinical applications in the treatment of psychiatric disorders in which glutamatergic transmission is reduced or absent (see, e.g., Horak et al., J. of Neuroscience, 2004, 24(46), 10318-10325). In contrast, negative regulators may be useful as therapeutic agents with potential clinical applications in the treatment of psychiatric disorders in which glutamatergic transmission is pathologically increased (e.g., treatment-resistant depression). Oxysterols are derived from cholesterol and have been shown to potently and selectively modulate the function of NMDA receptors. There is a need for new and improved oxysterols that modulate NMDA receptors to prevent and treat conditions associated with NMDA expression and function. The compounds, compositions and methods described herein are directed to this end. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Horak et al., J. of Neuroscience, 2004, 24(46), 10318-10325 Summary of the Invention [Means for solving the problem]

[0004] Summary of the Invention Provided herein are substituted oxysterols useful for the prevention and / or treatment of a wide range of disorders, including but not limited to NMDA-mediated disorders.These compounds are expected to exhibit improved in vivo efficacy, pharmacokinetic (PK) properties, oral bioavailability, suitability for formulation, stability and / or safety compared to other oxysterols.Further provided are pharmaceutical compositions comprising the compounds of the invention and methods of their use and treatment. In one aspect, the compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is hydrogen or C 1~6 R is alkyl; 2 is C 1~6 alkyl, carbocyclyl or heterocyclyl; R 5 is absent or is hydrogen; [ka] represents a single or double bond, where [ka] When is a double bond, the other [ka] is a single bond, and R 5 does not exist. In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is C 1~6 In some embodiments, R 1 is a substitution C 1~6 In some embodiments, R 1 is unsubstituted C 1~6 In some embodiments, R 1 is methyl (e.g., -CH, -CF, or -CHOCH), ethyl, or isopropyl. 1 is methyl (e.g., -CH3) or ethyl (e.g., -CH2CH3). In some embodiments, R 2 is C 1~6 In some embodiments, R 2 is a substitution C 1~6 In some embodiments, R 2 is unsubstituted C 1~6 In some embodiments, R 2 is C 1~4 In some embodiments, R 2 is a substitution C 1~4 In some embodiments, R 2 is unsubstituted C 1~4 In some embodiments, R 2 is C 1~3In some embodiments, R 2 is a substitution C 1~3 In some embodiments, R 2 is unsubstituted C 1~3 In some embodiments, R 2 is methyl, ethyl (e.g., -CHCH, -CHCF, -CH(CH)(CF)), isopropyl, tertbutyl, or cyclopropyl. 2 is haloalkyl. In some embodiments, R 2 is -CH2CF3 or -CH(CH3)(CF3). In some embodiments, R 1 and R 2 is C 1~6 In some embodiments, R 1 is C 1~6 is alkyl, R 2 is C 1~6 In some embodiments, R is an alkyl, carbocyclyl, or heterocyclyl. 1 is methyl or ethyl, R 2 is unsubstituted or substituted C 1~6 In some embodiments, R 1 is methyl or ethyl, R 2 is carbocyclyl or heterocyclyl. In some embodiments, [ka] represents a single bond. In some embodiments, the compound of formula (I) has formula (IA) or formula (IB): : [ka] It is a compound of the formula: In some embodiments, the compound of formula (I) has formula (IBi) or formula (IB-ii): [ka] It is a compound of the formula: In some embodiments, the compound of formula (I) has the formula (IC): [ka] It is a compound of the formula: In some embodiments, the compound of formula (IC) has the formula (ICi) or (IC-ii): [ka] It is a compound of the formula: In some embodiments, the compound of formula (ICi) has the formula (ICia) or (ICib): [ka] It is a compound of the formula: In some embodiments, the compound of formula (IC-ii) has the formula (IC-ii-a) or (IC-ii-b): [ka] It is a compound of the formula: In some embodiments, R 2 is C 1~6 In some embodiments, R 2 is a substitution C 1~6 In some embodiments, R 2 is C 1~6 It is haloalkyl. In some embodiments, the compound of formula (I) has the formula (II): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound of formula (II) has formula (II-A) or formula (II-B): [ka] It is a compound of the formula: In some embodiments, the compound of formula (II) has formula (II-C) or formula (II-D): [ka] It is a compound of the formula: In some embodiments, the compound of formula (II) has the formula (II-E): [ka] It is a compound of the formula: In some embodiments, the compound of formula (II-E) has formula (II-Ei) or formula (II-E-ii): [ka] It is a compound of the formula: In some embodiments, the compound of formula (II-Ei) has the formula (II-Eia) or the formula (II-Eib): [ka] It is a compound of the formula: In some embodiments, the compound of formula (II-E-ii) has formula (II-E-ii-a) or formula (II-E-ii-b): [ka] It is a compound of the formula: In some embodiments, the compound of formula (I) has formula (VII): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound of formula (VII) has formula (VII-A) or formula (VII-B): [ka] It is a compound of the formula: In some embodiments, the compound of formula (VII) has formula (VII-C) or formula (VII-D): [ka] It is a compound of the formula: In some embodiments, the compound of formula (VII) has the formula (VII-E): [ka] It is a compound of the formula: In some embodiments, the compound of formula (VII-E) has formula (VII-Ei) or formula (VII-E-ii): [ka] It is a compound of the formula: In some embodiments, the compound of formula (VII-Ei) has the formula (VII-Eia) or the formula (VII-Eib): [ka] It is a compound of the formula: In some embodiments, the compound of formula (VII-E-ii) has formula (VII-E-ii-a) or formula (VII-E-ii-b): [ka] It is a compound of the formula: In some embodiments, the compound of formula (I) has formula (III): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound of formula (III) has formula (III-A) or formula (III-B): [ka] It is a compound of the formula: In some embodiments, the compound of formula (I) has formula (IV): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound of formula (IV) has formula (IV-A) or formula (IV-B): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 2 is carbocyclyl or heterocyclyl. In some embodiments, R 2 is carbocyclyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, R 2 is heterocyclyl. In some embodiments, R 2 is an oxygen-containing heterocycle (eg, tetrahydropyran). In some embodiments, the compound of formula (I) has the formula (V): [ka] or a pharma- ceutically acceptable salt thereof, wherein X is -CH2-, -O-, -S-, or -NR A - where m is an integer selected from 0, 1, 2, 3, 4 or 5; R A is hydrogen, alkyl, -C(O)R C , -C(O)N(R C )2 or -SO2N(R C ) 2; each R C is independently hydrogen, alkyl, aryl, or heteroaryl. In some embodiments, X is -CH2-, -O-, -S-, or -NH-. In some embodiments, the compound of formula (V) has formula (VAi) or formula (VA-ii): [ka] It is a compound of the formula: In some embodiments, the compound of formula (V) has the formula (VB): [ka] It is a compound of the formula: In some embodiments, X is -CH2-. In some embodiments, X is --O--. In some embodiments, m is 0, 1, 2 or 3. In some embodiments, the compound of formula (V) has the formula (VBi): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound of formula (V) has the formula (VC): [ka] It is a compound of the formula: In some embodiments, the compound of formula (I) has formula (VI): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound of formula (I) has formula (VI-A) or formula (VI-B): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 1 is C 1~6 In some embodiments, R 1 is methyl (e.g., -CH, -CF, or -CHOCH), ethyl, or isopropyl. 1is methyl, ethyl, or isopropyl. 1 is methyl (e.g., -CH). In some embodiments, R 1 is ethyl (e.g., -CH2CH3). In some embodiments, the compound of formula (I) is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0005] In one aspect, provided herein is a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula (I), or a pharma- ceutically acceptable salt thereof), and a pharma- ceutically acceptable carrier.

[0006] In certain aspects, provided herein are methods of inducing sedation or anesthesia, the methods comprising administering to a subject an effective amount of a compound described herein (e.g., a compound of Formula (I), or a pharma- ceutically acceptable salt thereof), or a pharmaceutical composition thereof.

[0007] In certain aspects, provided herein are methods for treating or preventing a disorder described herein, the methods comprising administering to a subject in need of such treatment or prevention an effective amount of a compound described herein (e.g., a compound of Formula (I), or a pharma- ceutically acceptable salt thereof), or a pharmaceutical composition thereof.

[0008] In some embodiments, the disorder is a gastrointestinal (GI) disorder, e.g., constipation, irritable blowel syndrome (IBS), inflammatory bowel disease (IBD) (e.g., ulcerative colitis, Crohn's disease), structural disorders affecting the GI, anal disorders (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas), colon polyps, cancer, colitis.

[0009] In some embodiments, the disorder is inflammatory bowel disease.

[0010] In some embodiments, the disorder is cancer, diabetes, or a sterol synthesis disorder.

[0011] In certain aspects, provided herein are methods for treating or preventing a CNS-related condition, comprising administering to a subject in need of said treatment or prevention an effective amount of a compound described herein (e.g., a compound of Formula (I), or a pharma- ceutically acceptable salt thereof), or a pharmaceutical composition thereof. In some embodiments, the CNS-related condition is an adjustment disorder, an anxiety disorder (including obsessive-compulsive disorder, post-traumatic stress disorder, and social phobia), a cognitive disorder (including Alzheimer's disease and other forms of dementia), a dissociative disorder, an eating disorder, a mood disorder (including depression (e.g., postpartum depression), bipolar disorder, dysthymic disorder, suicidal ideation), schizophrenia or other psychotic disorder (including schizoaffective disorder), a sleep disorder (including insomnia), a substance-related disorder, a personality disorder (including obsessive-compulsive personality disorder), an autism spectrum disorder (including Shank's group of These conditions include those with mutations to proteins (e.g. Shank3), neurodevelopmental disorders (including Rett syndrome, tuberous sclerosis syndrome), multiple sclerosis, disorders of sterol synthesis, pain (including acute and chronic pain), encephalopathies secondary to certain medical conditions (including hepatic encephalopathy and anti-NMDA receptor encephalitis), seizure disorders (including status epilepticus and monogenic forms of epilepsy, e.g. Dravet disease), stroke, traumatic brain injury, movement disorders (including Huntington's disease and Parkinson's disease), visual impairment, hearing loss and tinnitus.

[0012] In some embodiments, the disorder is a sterol synthesis disorder.

[0013] Other objects and advantages will become apparent to those skilled in the art from a consideration of the following detailed description, examples, and claims. definition chemical definition

[0014] Definitions of certain functional groups and chemical terms are detailed below. Chemical elements are identified according to the Periodic Table of the Elements (CAS version, Handbook of Chemistry and Physics, 75th Edition, inside cover), and certain functional groups are generally defined as set forth therein. Additionally, general rules of organic chemistry, as well as certain functional moieties and reactivities, are described in detail in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 1999; York,2001;Larock,Comprehensive Organic Transformations,VCH Publishers,Inc.,New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd ed., Cambridge University Press, Cambridge, 1987.

[0015] The compounds described herein may contain one or more asymmetric centers, and therefore may exist as various isomers, such as enantiomers and / or diastereomers.For example, the compounds described herein may be in the form of individual enantiomers, diastereomers or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers.Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention further includes the compounds described herein as individual isomers substantially free of other isomers, and alternatively as mixtures of various isomers.

[0016] The compounds described herein may also contain one or more isotopic substitutions. For example, H is: 1 H, 2 H (D or deuterium), and 3 H can be in any isotopic form, including T or tritium; 12 C. 13 C, and 14 It can be in any isotopic form, including C; O is 16 O and 18 It can be any isotopic form including O; and so forth.

[0017] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1~6 Alkyl" is C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 , and C 5~6 is intended to include alkyl of the formula:

[0018] The following terms are intended to have the meanings presented below with respect thereto and are useful in understanding the specification and the intended scope of the invention. In describing the present invention, which may include compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms, when present, have the following meanings unless otherwise indicated. As described herein, it should also be understood that any of the moieties defined hereafter may be substituted with various substituents, and each definition is intended to include such substituted moieties within the scope as indicated below. Unless otherwise stated, the term "substituted" shall be defined as indicated below. It should further be understood that the terms "group" and "radical" may be considered interchangeable as used herein. The articles "a" and "an" may be used herein to refer to one or more than one (i.e., at least one) grammatical object of the article. By way of example, "an analogue" means one analogue or more than one analogue.

[0019] "Aliphatic" refers to any group including alkyl, alkenyl, alkynyl, or aryl, as defined herein. or a carbocyclyl group.

[0020] "Alkyl" means the radical of a linear or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1~20 In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C 1~12 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1~10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1~9 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1~8 In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1~7 In some embodiments, an alkyl group has 1 to 6 carbon atoms (also referred to herein as "lower alkyl"). 1~6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1~5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1~4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1~3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1~2 In some embodiments, an alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C 2~6 "Alkyl"). C 1~6Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5) and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each occurrence of an alkyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents; for example, 1-5 substituents, 1-3 substituents or 1 substituent ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1~10 In certain embodiments, the alkyl group is a substituted C 1~10 Common abbreviations for alkyl include Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2).

[0021] As used herein, "alkylene", "alkenylene" and "alkynylene" refer to divalent radicals of alkyl, alkenyl and alkynyl groups, respectively. When a range or number of carbons is provided for a particular "alkylene", "alkenylene" and "alkynylene" group, it is understood that the range or number refers to the range or number of carbons in a divalent linear carbon chain. "Alkylene", "alkenylene" and "alkynylene" groups can be substituted or unsubstituted with one or more substituents as described herein.

[0022] "Alkylene" refers to an alkyl group from which two hydrogens have been removed to provide a divalent radical, which may be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), butylene (-CHCHCHCH-), pentylene (-CHCHCHCHCHCH-), hexylene (-CHCHCHCHCHCHCH-), and the like. Exemplary substituted alkylene groups, e.g., alkylene groups substituted with one or more alkyl (methyl) groups, include substituted methylene (-CH(CH)-, (-C(CH)-), substituted ethylene (-CH( Examples of propylene include, but are not limited to, substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2-), and substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-).

[0023] "Alkenyl" refers to the radical of a straight-chain or branched-chain hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) ("C 2~20 In certain embodiments, an alkenyl group does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C 2~10 In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C 2~7In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, an alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., 2-butenyl) or terminal (e.g., 1-butenyl). C 2~4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each occurrence of an alkenyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1-5 substituents, 1-3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2~10 In certain embodiments, the alkenyl group is a substituted C 2~10 It is alkenyl.

[0024] "Alkenylene" refers to an alkenyl group in which two hydrogens are removed to provide a divalent radical, which may be substituted or unsubstituted. Exemplary divalent unsubstituted alkenylene groups include, but are not limited to, ethenylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenylene groups, e.g., alkenylene groups substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted ethylene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propylene (e.g., -C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), and the like.

[0025] "Alkynyl" refers to an alkynyl group containing 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one A radical of a straight or branched chain hydrocarbon group having 1 or more carbon-carbon double bonds (e.g., 1, 2, 3 or 4 carbon-carbon double bonds) ("C 2~20 In certain embodiments, an alkynyl group does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms ("C 2~10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2~6In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, an alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (e.g., 2-butynyl) or terminal (e.g., 1-butynyl). C 2~4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 Alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Further examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each occurrence of an alkynyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents; for example, 1-5 substituents, 1-3 substituents, or 1 substituent ("substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2~10 In certain embodiments, the alkynyl group is a substituted C 2~10 It is alkynyl.

[0026] "Alkynylene" refers to a straight-chain alkynyl group in which two hydrogens are removed to provide a divalent radical, which may be substituted or unsubstituted. Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like.

[0027] The term "heteroalkyl," as used herein, refers to an alkyl group, as defined herein, that further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) in the parent chain, where the one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or the one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group having 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~10 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~9 In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~8 In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~7 In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ("heteroC 1~6 In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("heteroalkyl"). RO C 1~5 In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms ("heteroC 1~4 In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom ("heteroC 1~3 In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom ("heteroC 1~2In some embodiments, the heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroC1 alkyl"). In some embodiments, the heteroalkyl group is a saturated group having 2-6 carbon atoms and 1 or 2 heteroatoms ("heteroC 2~6 Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted ("unsubstituted heteroalkyl") or substituted with one or more substituents ("substituted heteroalkyl"). In certain embodiments, a heteroalkyl group is an unsubstituted heteroC 1~10 In certain embodiments, the heteroalkyl group is a substituted heteroalkyl group. 1~10 It is an alkyl.

[0028] The term "heteroalkenyl," as used herein, refers to an alkenyl group, as defined herein, further containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), where the one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or the one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, a heteroalkenyl group refers to a group having 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~10 In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~9 In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~8 In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~7In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms ("heteroC 2~6 In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2~5 In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2~4 In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond and one heteroatom ("heteroC 2~3 In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2~6 Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted ("unsubstituted heteroalkenyl") or substituted with one or more substituents ("substituted heteroalkenyl"). In certain embodiments, a heteroalkenyl group is an unsubstituted heteroC 2~10 In certain embodiments, the heteroalkenyl group is a substituted heteroC 2~10 It is alkenyl.

[0029] The term "heteroalkynyl," as used herein, refers to an alkynyl group, as defined herein, further containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), where the one or more heteroatoms are not spaced apart from adjacent carbon atoms in the parent carbon chain. An atom is inserted between the carbon atom and the parent molecule, i.e., the point of attachment, and / or one or more heteroatoms are inserted between the carbon atom and the parent molecule. In certain embodiments, a heteroalkynyl group refers to a group having 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~10 In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~9 In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~8 In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~7 In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms ("heteroC 2~6 In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2~5 In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2~4 In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond and one heteroatom ("heteroC 2~3 In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2~6Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted ("unsubstituted heteroalkynyl") or substituted with one or more substituents ("substituted heteroalkynyl"). In certain embodiments, a heteroalkynyl group is an unsubstituted heteroC 2~10 In certain embodiments, the heteroalkynyl group is a substituted heteroC 2~10 It is alkynyl.

[0030] As used herein, "alkylene", "alkenylene", "alkynylene", "heteroalkylene", "heteroalkenylene" and "heteroalkynylene" refer to the divalent radicals of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl and heteroalkynyl groups, respectively. When a range or number of carbons is provided for a particular "alkylene", "alkenylene", "alkynylene", "heteroalkylene", "heteroalkenylene" or "heteroalkynylene" group, it is understood that the range or number refers to the range or number of carbons in the divalent linear carbon chain. "Alkylene", "alkenylene", "alkynylene", "heteroalkylene", "heteroalkenylene" and "heteroalkynylene" groups can be substituted or unsubstituted with one or more substituents as described herein.

[0031] "Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system ("C 6~14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C14 "Aryl"; e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, where the attachment radical or point of attachment is on the aryl ring, and in such cases the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Exemplary aryl groups include acetonitrile, ... Examples of aryl groups include, but are not limited to, groups derived from tolylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene and trinaphthalene. In particular, aryl groups include phenyl, naphthyl, indenyl and tetrahydronaphthyl. Unless otherwise specified, each occurrence of aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, the aryl group is an unsubstituted C 6~14 In certain embodiments, the aryl group is a substituted C 6~14 It is aryl.

[0032] In certain embodiments, the aryl group is substituted with one or more groups selected from halo, C1-C8 alkyl, C1-C8 haloalkyl, cyano, hydroxy, C1-C8 alkoxy, and amino.

[0033] Representative examples of substituted aryl include: [ka] Here, R 56 and R57 can be hydrogen, and R 56 and R 57 At least one of each independently represents C1-C8 alkyl, C1-C8 haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 , N.R. 58 SOR 59 , N.R. 58 SO2R 59 , COO alkyl, COO aryl, CONR 58 R 59 ,CONR 58 OR 59 , N.R. 58 R 59 , SO2NR 58 R 59 , S-alkyl, SOalkyl, SO2alkyl, Saryl, SOaryl, SO2aryl; or R 56 and R 57 may be linked to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms, optionally including one or more heteroatoms selected from the group N, O or S. 60 and R 61 are independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, substituted C6-C 10 It is aryl, 5- to 10-membered heteroaryl or substituted 5- to 10-membered heteroaryl.

[0034] A "fused aryl" refers to an aryl having two of its ring carbons in common with a second aryl or heteroaryl ring, or a carbocyclyl or heterocyclyl ring.

[0035] "Aralkyl" is a subset of alkyl and aryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group.

[0036] "Heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic arrangement) in which ring carbon atoms and one to four ring heteroatoms are provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (see "5-10 membered heteroaryl"). "aryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, where valence permits. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused with one or more carbocyclyl or heterocyclyl groups, where the point of attachment is on the heteroaryl ring, and in such cases the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups, where the point of attachment is on the aryl ring or on the heteroaryl ring, and in such cases the number of ring members continues to refer to the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on the ring containing the heteroatom (e.g., 2-indolyl) or on the ring without the heteroatom (e.g., 5-indolyl).

[0037] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system in which ring carbon atoms and 1-4 ring heteroatoms are provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system in which ring carbon atoms and 1-4 ring heteroatoms are provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system in which ring carbon atoms and 1-4 ring heteroatoms are provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heteroaryl has one ring heteroatom selected from nitrogen, oxygen and sulfur. Unless otherwise specified, each occurrence of a heteroaryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0038] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0039] Representative examples of heteroaryls include the following: [ka] where each Z is carbonyl, N, NR 65 , O and S; R 65 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl.

[0040] "Heteroaralkyl" is a subset of alkyl and heteroaryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted heteroaryl group.

[0041] "Carbocyclyl" or "carbocyclic" means a ring system having 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10 Carbocyclyl). Exemplary C 3~6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C 3~8 The carbocyclyl group is the above-mentioned C 3~6Examples of carbocyclyl groups include, but are not limited to, cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. 3~10 The carbocyclyl group is the above-mentioned C 3~8 Carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), Decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like. As the foregoing examples are illustrated, in certain embodiments, a carbocyclyl group is monocyclic ("monocyclic carbocyclyl") or includes fused, bridged, or spiro ring systems (e.g., bicyclic systems ("bicyclic carbocyclyl")), which may be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, where the point of attachment is on the carbocyclyl ring, and in such cases the number of carbons continues to refer to the number of carbons in the carbocyclyl ring system. Unless otherwise specified, each occurrence of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, a carbocyclyl group is an unsubstituted C 3~10 In certain embodiments, the carbocyclyl group is a substituted C 3~10 It is a carbocyclyl.

[0042] In some embodiments, "carbocyclyl" refers to a monocyclic saturated carbocyclyl group having 3 to 10 ring carbon atoms ("C 3~10In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5~6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5~10 "Cycloalkyl"). C 5~6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3~6 Examples of cycloalkyl groups include the above-mentioned C 5~6 Cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4). 3~8 Examples of cycloalkyl groups include the above-mentioned C 3~6 Cycloalkyl groups include cycloalkyl groups, as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each occurrence of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C 3~10 In certain embodiments, the cycloalkyl group is a substituted C 3~10 It is cycloalkyl.

[0043] "Heterocyclyl" or "heterocyclic" refers to the radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, when valence permits. Heterocyclyl groups may be monocyclic ring systems ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused with one or more carbocyclyl groups, where the point of attachment is on the carbocyclyl or heterocyclyl ring, or on a ring system in which a heterocyclyl ring as defined above is fused with one or more aryl or heteroaryl groups, where the point of attachment is on the heterocyclyl ring, in which case the number of ring members continues to refer to the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each occurrence of heterocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is an unsubstituted 3-10 membered heterocyclyl. In embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0044] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, a 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0045] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclic rings) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclic rings) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0046] "Hetero", when used to describe a compound or a group present on a compound, means that one or more carbon atoms in the compound or group are replaced by a nitrogen, oxygen or sulfur heteroatom. Hetero can apply to any of the hydrocarbyl groups described above having 1 to 5, especially 1 to 3, heteroatoms, such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g., heteroaryl, cycloalkenyl, e.g., cycloheteroalkenyl, etc.

[0047] "Acyl" means -C(O)R 20 This refers to the radical, where R 20 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein. "Alkanoyl" refers to any group represented by R 20 is an acyl group, where the aryl group is a group other than hydrogen. Representative acyl groups include formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), --C(O)-C1-C8 alkyl, -C(O)-(CH2) t (C6-C 10 Aryl), -C(O)-(CH2) t (5-10 membered heteroaryl), -C(O)-(CH2) t (C3-C 10 Cycloalkyl) and -C(O)-(CH2) t (4-10 membered heterocyclyl) (t is an integer from 0 to 4).21 is C1-C8 alkyl substituted with halo or hydroxy; or C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy.

[0048] "Alkoxy" means -OR 29 The R 29 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e. having 1 to 6 carbon atoms. Further particular alkoxy groups have 1 to 4 carbon atoms.

[0049] In certain embodiments, R 29 is amino, substituted amino, C6-C 10 Aryl, aryloxy, carboxyl, cyano, C3~C 10 A group having one or more substituents selected from the group consisting of cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2-, and aryl-S(O)2-, for example, 1 to 5 substituents, particularly 1 to 3 substituents, and especially 1 substituent. Exemplary "substituted alkoxy" groups include -O-(CH2) t (C6~C10 Aryl), -O-(CH2) t (5-10 membered heteroaryl), -O-(CH2) t (C3~C 10 Cycloalkyl) and -O-(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl or heterocyclyl group present may itself be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy. Particularly exemplary "substituted alkoxy" groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH and -OCH2CH2NMe2.

[0050] "Amino" refers to the -NH2 radical.

[0051] "Substituted amino" refers to a group of the formula -N(R 38 )2, where R 38 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino protecting group, where R 38 At least one of R is not hydrogen. 38 are independently hydrogen, C1-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl or C3-C 10 cycloalkyl; or C1-C8 alkyl substituted with halo or hydroxy; C3-C8 alkenyl substituted with halo or hydroxy; C3-C8 alkynyl substituted with halo or hydroxy, or -(CH2) t (C6~C10 Aryl), -(CH2) t (5-10 membered heteroaryl), -(CH2) t (C3~C 10 Cycloalkyl) or -(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 8, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; or both R 38 The groups are linked to form an alkylene group.

[0052] Exemplary "substituted amino" groups include -NR 39 -C1-C8 alkyl, -NR 39 -(CH2) t (C6~C 10 Aryl), -NR 39 -(CH2) t (5-10 membered heteroaryl), -NR 39 -(CH2) t (C3~C 10 Cycloalkyl) and -NR 39 -(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, e.g., 1 or 2, and each R 39independently represent H or C1-C8 alkyl; any alkyl group present may itself be substituted by halo, substituted or unsubstituted amino or hydroxy; any aryl, heteroaryl, cycloalkyl or heterocyclyl group present may itself be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy. For the avoidance of doubt, the term "substituted amino" includes alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino and substituted dialkylamino groups as defined below. Substituted amino encompasses both mono- and di-substituted amino groups.

[0053] "Carboxy" refers to the radical -C(O)OH.

[0054] "Cyano" refers to the radical -CN.

[0055] "Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). In certain embodiments, a halo group is fluoro or chloro.

[0056] "Hydroxy" refers to the radical -OH.

[0057] "Nitro" refers to the radical -NO2.

[0058] "Cycloalkylalkyl" refers to an alkyl radical in which the alkyl group is substituted with a cycloalkyl group. Exemplary cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl.

[0059] "Heterocyclylalkyl" refers to an alkyl radical in which the alkyl group is substituted with a heterocyclyl group. Exemplary heterocyclylalkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, and the like.

[0060] A "nitrogen-containing heterocyclyl" group refers to a 4- to 7-membered non-aromatic ring group containing at least one nitrogen atom, including, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazines (e.g., N-methylpiperazine). Particular examples include azetidine, piperidone, and piperazone.

[0061] "Thioketo" refers to the group =S.

[0062] As defined herein, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted (e.g., a "substituted" or "unsubstituted" alkyl, a "substituted" or "unsubstituted" alkenyl, a "substituted" or "unsubstituted" alkynyl, a "substituted" or "unsubstituted" carbocyclyl, a "substituted" or "unsubstituted" heterocyclyl, a "substituted" or "unsubstituted" aryl, or a "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted", whether preceded by the term "optionally" or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that, when substituted, gives rise to a stable compound, e.g., a compound that does not spontaneously undergo transformation (e.g., by rearrangement, cyclization, elimination, or other reaction). Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when two or more positions in any given structure are substituted, the substituents are the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that form a stable compound. The present invention contemplates any and all such combinations to arrive at a stable compound. For purposes of the present invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents as described herein that satisfy the valence of the heteroatom and thus form a stable moiety.

[0063] Exemplary carbon atom substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-S C(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2Raa , -OP(=O)2R aa , -P(=O)(R aa )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl and 5-14 membered heteroaryl, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd Is it substituted with a group; Or the two geminal hydrogens on a carbon atom can be substituted with the groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb , or =NOR cc Replaced by; R aa Each occurrence of is independently 1~10 Alkyl, C1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R aa groups linked together form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently represents 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R bb Each occurrence of is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R bbgroups linked together form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently represents 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R cc Each occurrence of is independently hydrogen, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R cc groups linked together form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently represents 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R dd Each occurrence of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NRff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R e e , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)2R ee , -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg or two geminal R dd The substituents may be taken together to form =O or =S; R ee Each occurrence of is independently 1~6 Alkyl, C1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R ff Each occurrence of is independently hydrogen, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl and 5-10 membered heteroaryl, or two R ff groups linked together form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently represents 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R gg Each occurrence of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 Alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C 1~6 Alkyl)3 + X - , -NH(C 1~6 Alkyl)2 + X - , -NH2(C 1~6 Alkyl) + X - , -NH3 + X - , -N(OC 1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6 alkyl), -NH(OH), -SH, -SC1~6 Alkyl, -SS(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -CO2H, -CO2(C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -C(=O)NH2, -C(=O)N(C 1~6 alkyl)2, -OC(=O)NH(C 1~6 alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 Alkyl)C(=O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1~6 alkyl), -OC(=NH)(C 1~6 alkyl), -OC(=NH)OC 1~6 Alkyl, -C(=NH)N(C 1~6 alkyl)2, -C(=NH)NH(C 1~6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1~6 alkyl)2, -OC(NH)NH(C 1~6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1~6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1~6 Alkyl), -SO2N(C 1~6 Alkyl)2, -SO2NH(C 1~6 Alkyl), -SO2NH2, -SO2C 1~6 Alkyl, -SO2OC 1~6 Alkyl, -OSO2C 1~6 Alkyl, -SOC 1~6 Alkyl, -Si(C 1~6 alkyl)3, -OSi(C 1~6 Alkyl)3-C(=S)N(C 1~6 alkyl)2, C(=S)NH(C 1~6 alkyl), C(=S)NH2, -C(=O)S(C 1~6Alkyl), -C(=S)SC 1~6 Alkyl, -SC(=S)SC 1~6 Alkyl, -P(=O)2(C 1~6 alkyl), -P(=O)(C 1~6 alkyl)2, -OP(=O)(C 1~6 Alkyl)2, -OP(=O)(OC 1~6 Alkyl)2, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl; or two geminal R gg The substituents together may form =O or =S; where X - is the counter ion It is.

[0064] A "counterion" or "anionic counterion" is a negatively charged group that associates with a cationic quaternary amino group to maintain electrical neutrality. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HSO4 - , SO4 -2 Included are sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.) and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0065] Nitrogen atoms may be substituted or unsubstituted, where valences permit, and may include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, -OR. aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl and 5-14 membered heteroaryl; or two R cc The groups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently represents 0, 1, 2, 3, 4, or 5 R dd is substituted with a R aa , R bb , R cc and R dd is as defined above.

[0066] These and other exemplary substituents are described in detail in the detailed description, examples, and claims. It is not intended that the invention be limited in any manner by the exemplary recitation of substituents above. Other definitions

[0067] The term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., within the scope of sound medical judgment, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and inorganic and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid) or by using other methods used in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, and glucoheptonate. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and the like. + (C 1~4 Representative alkali or alkaline earth metal salts include the sodium, lithium, potassium, calcium, magnesium, and the like salts. Further pharma- ceutically acceptable salts include the salts of non-toxic ammonium, quaternary ammonium, and amine cations, formed when appropriate with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0068] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, e.g., mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs). In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0069] Disease, disorder, and condition are used interchangeably herein.

[0070] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions taken while a subject is suffering from a particular disease, disorder, or condition that reduce the severity of the disease, disorder, or condition or delay or slow the progression of the disease, disorder, or condition ("therapeutic treatment"), and also contemplate actions taken before a subject begins to suffer from a particular disease, disorder, or condition ("prophylactic treatment").

[0071] In general, the "effective amount" of a compound refers to an amount sufficient to induce a desired biological response.As will be understood by those skilled in the art, the effective amount of the compound of the present invention may vary depending on factors such as the desired biological goal, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the age, health status, and condition of the subject.The effective amount includes therapeutic treatment and prophylactic treatment.

[0072] As used herein, unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of the disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, an amount that reduces or avoids the symptoms or causes of a disease or condition, or an amount that enhances the therapeutic efficacy of another therapeutic agent.

[0073] As used herein, unless otherwise specified, a "prophylactically effective amount" of a compound means A sufficient amount to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or to prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of the disease, disorder or condition. The term "prophylactically effective amount" can include an amount that improves overall prophylaxis, or an amount that enhances the prophylactic efficacy of another prophylactic agent. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0074] Detailed Description of Certain Embodiments of the Invention [1] As broadly described herein, the present invention provides oxysterols useful for the prevention and / or treatment of a wide range of disorders, including but not limited to NMDA-mediated disorders. These compounds are expected to exhibit improved in vivo efficacy, pharmacokinetic (PK) properties, oral bioavailability, suitability for formulation, stability and / or safety compared to other oxysterols. compound

[0075] In one aspect, the present invention provides a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is hydrogen or C 1~6 R is alkyl; 2 is C 1~6 alkyl, carbocyclyl or heterocyclyl; R 5 is absent or is hydrogen; [ka] represents a single or double bond, where [ka] When is a double bond, the other [ka] is a single bond, and R 5 does not exist. In some embodiments, R 1 is hydrogen. In some embodiments, the compound of formula (I) has the formula (X): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 2 is C 1~6 alkyl, carbocyclyl or heterocyclyl; R 5 is absent or is hydrogen; [ka] represents a single or double bond, where [ka] When is a double bond, the other [ka] is a single bond, and R 5 does not exist. In some embodiments, R 1 is C 1~6 In some embodiments, R 1 is a substitution C 1~6 In some embodiments, R 1 is unsubstituted C 1~6 In some embodiments, R 1 is methyl (e.g., -CH3, -CF3 or -CH2OCH3), ethyl or isopropyl. In some embodiments, R 1 is methyl (e.g., -CH3) or ethyl (e.g., -CH2CH3). In some embodiments, R 2 is C 1~6In some embodiments, R 2 is a substitution C 1~6 In some embodiments, R 2 is unsubstituted C 1~6 In some embodiments, R 2 is methyl (e.g., -CH), ethyl (e.g., -CHCH, -CHCF, -CH(CH)(CF)), isopropyl, tertbutyl, or cyclopropyl. 2 is haloalkyl. In some embodiments, R 2 is -CHCF or -CH(CH)(CF). In some embodiments, R 1 and R 2 is C 1~6 In some embodiments, R 1 is C 1~6 is alkyl, R 2 is C 1~6 In some embodiments, R 1 is methyl or ethyl, R 2 is unsubstituted or substituted C 1~6 In some embodiments, R is an alkyl group (e.g., haloalkyl). 1 is methyl or ethyl, R 2 is carbocyclyl or heterocyclyl. In some embodiments, [ka] represents a single bond.

[0076] In some embodiments, the compound of formula (I) has formula (IA) or formula (IB): [ka] It is a compound of the formula: In some embodiments, the compound of formula (I) has formula (IBi) or formula (IB-ii): [ka] It is a compound of the formula: In some embodiments, the compound of formula (I) has the formula (IC): [ka] It is a compound of the formula: In some embodiments, the compound of formula (IC) has formula (ICi) or (IC-ii): [ka] It is a compound of the formula: In some embodiments, the compound of formula (ICi) has the formula (ICia) or (ICib): [ka] It is a compound of the formula: In some embodiments, the compound of formula (IC-ii) has the formula (IC-ii-a) or (IC-ii-b): [ka] It is a compound of the formula: In some embodiments, R 2 is C 1~6 In some embodiments, R 2 is a substitution C 1~6 In some embodiments, the compound of formula (I) has formula (II): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound of formula (II) has formula (II-A) or formula (II-B): [ka] It is a compound of the formula: In some embodiments, the compound of formula (II) has formula (II-C) or formula (II-D): [ka] It is a compound of the formula: In some embodiments, the compound of formula (II) has the formula (II-E): [ka] It is a compound of the formula: In some embodiments, the compound of formula (II-E) has formula (II-Ei) or formula (II-E-ii): [ka] It is a compound of the formula: In some embodiments, the compound of formula (II-Ei) has the formula (II-Eia) or the formula (II-Eib): [ka] It is a compound of the formula: In some embodiments, the compound of formula (II-E-ii) has formula (II-E-ii-a) or formula (II-E-ii-b): [ka] It is a compound of the formula: In some embodiments, the compound of formula (I) has formula (VII): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound of formula (VII) has formula (VII-A) or formula (VII-B): [ka] It is a compound of the formula: In some embodiments, the compound of formula (VII) has formula (VII-C) or formula (VII-D): [ka] It is a compound of the formula: In some embodiments, the compound of formula (VII) has the formula (VII-E): [ka] It is a compound of the formula: In some embodiments, the compound of formula (VII-E) has formula (VII-Ei) or formula (VII-E-ii): [ka] It is a compound of the formula: In some embodiments, the compound of formula (VII-Ei) has the formula (VII-Eia) or the formula (VII-Eib): [ka] It is a compound of the formula: In some embodiments, the compound of formula (VII-E-ii) has formula (VII-E-ii-a) or formula (VII-E-ii-b): [ka] It is a compound of the formula: In some embodiments, the compound of formula (I) has formula (III): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound of formula (III) has formula (III-A) or formula (III-B): [ka] It is a compound of the formula: In some embodiments, the compound of formula (I) has formula (IV): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound of formula (IV) has formula (IV-A) or formula (IV-B): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 2 is carbocyclyl or heterocyclyl. In some embodiments, R 2 is carbocyclyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In some embodiments, R 2 is heterocyclyl. In some embodiments, R 2 is an oxygen-containing heterocycle (eg, tetrahydropyran). In some embodiments, the compound of formula (I) has the formula (V): [ka] or a pharma- ceutically acceptable salt thereof, wherein X is -CH2-, -O-, -S-, or -NR A - where m is an integer selected from 0, 1, 2, 3, 4 or 5; R A is hydrogen, alkyl, -C(O)R C , -C(O)N(R C )2 or -SO2N(R C ) 2; each R C is independently hydrogen, alkyl, aryl, or heteroaryl. In some embodiments, X is -CH2-, -O-, -S-, or -NH-. In some embodiments, the compound of formula (V) has formula (VAi) or formula (VA-ii): [ka] It is a compound of the formula: In some embodiments, the compound of formula (V) has the formula (VB): [ka] It is a compound of the formula: In some embodiments, X is -CH2-. In some embodiments, X is --O--. In some embodiments, m is 0, 1, 2 or 3. In some embodiments, the compound of formula (V) has the formula (VBi): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound of formula (V) has the formula (VC): [ka] It is a compound of the formula: In some embodiments, the compound of formula (I) has formula (VI): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound of formula (VI) has formula (VI-A) or formula (VI-B): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, R 1 is C 1~6 In some embodiments, R 1 is methyl (e.g., -CH3, -CF3 or -CH2OCH3), ethyl or isopropyl. In some embodiments, R 1 is methyl, ethyl or isopropyl. In some embodiments, the compound of formula (I) is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound of formula (I) is [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof. Pharmaceutical Compositions

[0077] In another aspect, the present invention provides pharmaceutical compositions comprising a pharma- ceutically acceptable carrier and an effective amount of a compound described herein (e.g., a compound of Formula (I)).

[0078] When the compounds provided herein are used as pharmaceuticals, they are usually administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and contain at least one active compound.

[0079] In one embodiment, with respect to the pharmaceutical composition, the carrier is a parenteral carrier, an oral or a topical carrier.

[0080] The present invention also relates to a compound described herein (eg, a compound of formula (I) or a pharmaceutical composition thereof) for use as a pharmaceutical or medicine.

[0081] Generally, the compounds provided herein are administered in effective amounts.The amount of compound actually administered is typically determined by the physician in light of the relevant circumstances, including the condition being treated, the route of administration selected, the actual compound being administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0082] The pharmaceutical compositions provided herein can be administered by various routes, including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal.Depending on the intended delivery route, the compounds provided herein are preferably formulated as injectable compositions, or oral compositions, or ointments, lotions or patches (all for transdermal administration).

[0083] Compositions for oral administration may take the form of a bulk liquid solution or suspension or a bulk powder. More commonly, however, the compositions are provided in unit dosage form to facilitate accurate dosing. The term "unit dosage form" refers to a unit dose for human subjects and other mammals. It refers to physically discrete units suitable for a quantity, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect together with suitable pharmaceutical excipients. Typical unit dosage forms include pre-measured, pre-filled ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc., in the case of solid compositions. In such compositions, the compound is usually a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various vehicles or carriers and processing aids that help form the desired dosage form.

[0084] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors, etc. Solid forms may include, for example, any of the following ingredients or compounds of a similar nature: binders (e.g., microcrystalline cellulose, gum tragacanth, or gelatin); excipients (e.g., starch or lactose); disintegrating agents (e.g., alginic acid, Primogel, or corn starch); lubricants (e.g., magnesium stearate); glidants (e.g., colloidal silicon dioxide); sweetening agents (e.g., sucrose or saccharin); or flavoring agents (e.g., peppermint, methyl salicylate, or orange flavoring).

[0085] Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline or other injectable carriers known in the art. Conventionally, the active compound in such compositions is typically a minor component, often about 0.05-10% by weight, with the remainder being the injectable carrier and the like.

[0086] Transdermal compositions are generally formulated as topical ointments or creams, usually containing the active ingredient(s) in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, more preferably from about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredient is typically mixed with a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream, for example, with an oil-in-water cream base. Such transdermal formulations are well known in the art and generally include additional ingredients that enhance the skin penetration or stability of the active ingredient or its formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.

[0087] The compounds provided herein can also be administered by a transdermal device.Thus, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type or of a solid matrix variety.

[0088] The components described above for orally administrable, injectable, or topically administrable compositions are merely representative. Other materials, as well as processing techniques, etc., are set forth in Part 8 of Remington's Pharmaceutical Sciences, 17th Edition, 1985, Mack Publishing Company, Easton, Pennsylvania (herein incorporated by reference).

[0089] The above-described components for orally administrable compositions, injectable compositions or topically administrable compositions are merely representative. Other materials and processing techniques are shown in Part 8 of Remington's The Science and Practice of Pharmacy, 21st edition, 2005, Publisher: Lippincott Williams & Wilkins (herein incorporated by reference).

[0090] The compounds of the invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0091] The present invention also relates to pharma- ceutically acceptable formulations of the compounds described herein (e.g., compounds of formula (I)). In one embodiment, the formulation comprises water. In another embodiment, the formulation further comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, which consist of 6, 7, and 8 α-1,4-linked glucose units, respectively, optionally containing one or more substituents on the attached sugar moiety, including, but not limited to, methylation, hydroxyalkylation, acylation, and sulfoalkyl ether substitution. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, also known as Captisol®. See, e.g., U.S. Pat. No. 5,376,645. In certain embodiments, the formulation comprises hexapropyl-β-cyclodextrin. In a more specific embodiment, the formulation includes hexapropyl-β-cyclodextrin (10-50% in water).

[0092] The present invention also relates to pharma- ceutically acceptable acid addition salts of the compounds described herein (e.g., compounds of formula (I)). Acids that can be used to prepare pharma- ceutically acceptable salts are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions (e.g., hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, and the like).

[0093] The following formulation examples illustrate representative pharmaceutical compositions that may be prepared according to the present invention, but the present invention is not limited to the following pharmaceutical compositions.

[0094] Exemplary Formulation 1 - Tablets: A compound described herein (e.g., a compound of Formula (I) or a pharma- ceutically acceptable salt thereof) can be mixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg of active compound per tablet) in a tablet press.

[0095] Exemplary Formulation 2 - Capsules: A compound described herein (e.g., a compound of Formula (I) or a pharma- ceutically acceptable salt thereof) can be mixed as a dry powder with a starch diluent in an approximate 1:1 weight ratio. The mixture is filled into 250 mg capsules (125 mg of active compound per capsule).

[0096] Exemplary Formulation 3-Solution: A compound described herein (e.g., a compound of Formula (I) or a pharma- ceutically acceptable salt thereof) (125 mg) can be mixed with sucrose (1.75 g) and xanthan gum (4 mg), the resulting mixture can be blended, passed through a No. 10 mesh US sieve, and then mixed with a previously prepared aqueous solution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50 mg). Sodium benzoate (10 mg), flavor, and color are diluted with water and added with stirring. Sufficient water can then be added to bring the total volume to 5 mL.

[0097] Exemplary Formulation 4 - Tablets: A compound described herein (e.g., a compound of Formula (I) or a pharma- ceutically acceptable salt thereof) can be mixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg of active compound) in a tablet press.

[0098] Exemplary Formulation 5 - Injection: A compound described herein (e.g., a compound of Formula (I) or a pharma- ceutically acceptable salt thereof) can be dissolved or suspended in an injectable aqueous medium, which is sterile buffered saline, to a concentration of approximately 5 mg / mL.

[0099] Exemplary Formulation 6 - Tablets: A compound described herein (e.g., a compound of Formula (I) or a pharma- ceutically acceptable salt thereof) can be mixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into 90-150 mg tablets (30-50 mg of active compound per tablet) in a tablet press.

[0100] Exemplary Formulation 7 - Tablets: A compound described herein (e.g., a compound of Formula (I) or a pharma- ceutically acceptable salt thereof) may be mixed as a dry powder with a dry gelatin binder, possibly in an approximate 1:2 weight ratio. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into 30-90 mg tablets (10-30 mg of active compound per tablet) in a tablet press.

[0101] Exemplary Formulation 8 - Tablets: A compound described herein (e.g., a compound of Formula (I) or a pharma- ceutically acceptable salt thereof) can be mixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into 0.3-30 mg tablets (0.1-10 mg of active compound per tablet) in a tablet press.

[0102] Exemplary Formulation 9 - Tablets: A compound described herein (e.g., a compound of Formula (I) or a pharma- ceutically acceptable salt thereof) can be mixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into 150-240 mg tablets (50-80 mg of active compound per tablet) in a tablet press.

[0103] Exemplary Formulation 10 - Tablets: A compound described herein (e.g., a compound of Formula (I) or a pharma- ceutically acceptable salt thereof) can be mixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into 270-450 mg tablets (90-150 mg of active compound per tablet) in a tablet press.

[0104] Injectable dose levels range from about 0.1 mg / kg / hour to at least 10 mg / kg / hour, all over a period of about 1 to about 120 hours, particularly 24 to 96 hours. A preloading bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady state levels. The maximum total dose is not expected to exceed about 2 g / day for a 40-80 kg human patient.

[0105] For the prevention and / or treatment of long-term symptoms, the regimen for treatment usually extends over months or years, so oral administration is preferred for patient convenience and tolerance. For oral administration, oral administration 1-5 times, particularly 2-4 times, typically 3 times per day is a typical regimen. When using these dosing patterns, each dose provides about 0.01 to about 20 mg / kg of the compound provided herein, with preferred doses providing about 0.1 to about 10 mg / kg, particularly about 1 to about 5 mg / kg, respectively.

[0106] Transdermal doses are generally selected to provide blood levels similar to or lower than those achieved using injection doses.

[0107] When used to prevent the development of CNS disorder, the compounds provided herein can typically be administered to subjects at risk of developing the condition at the dosage levels described above, with the advice and under the supervision of a physician.Subjects at risk of developing a particular condition generally include subjects with a family history of the condition, or subjects identified by genetic testing or screening as being particularly susceptible to developing the condition. Treatment and Use

[0108] The compounds of the present invention (e.g., compounds of formula (I) and pharma- ceutically acceptable salts thereof as described herein) are typically designed to modulate the function of NMDA and thus act as oxysterols, for example, for the treatment and prevention of CNS-related conditions in a subject. In some embodiments, the compounds described herein (e.g., compounds of formula (I) and pharma- ceutically acceptable salts thereof as described herein) are typically designed to penetrate the blood-brain barrier (e.g., designed to be transported across the blood-brain barrier). Modulation, as used herein, refers to, for example, inhibition or enhancement of the function of the NMDA receptor. In certain embodiments, the compounds described herein (e.g., compounds of formula (I) and pharma- ceutically acceptable salts thereof) can act as NMDA negative allosteric modulators (NAMs) and inhibit the function of the NMDA receptor. In certain embodiments, the compounds of the present invention, such as compounds of formula (I) or pharma- ceutically acceptable salts thereof, may act as positive allosteric modulators (PAMs) of NMDA and enhance the function of the NMDA receptor. In certain ceratin embodiments, the compounds described herein (e.g., compounds of formula (I) and pharma-ceutically acceptable salts thereof) modulate the function of NMDA but do not act as negative allosteric modulators (NAMs) or positive allosteric modulators (PAMs) of NMDA.

[0109] In some embodiments, the disorder is cancer. In some embodiments, the disorder is diabetes. In some embodiments, the disorder is a sterol synthesis disorder. In some embodiments, the disorder is a gastrointestinal (GI) disorder, such as constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) (e.g., ulcerative colitis, Crohn's disease), structural disorders affecting the GI, anal disorders (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas), colon polyps, cancer, colitis. In some embodiments, the disorder is inflammatory bowel disease.

[0110] In some embodiments, the disorder is Smith-Lemli-Opitz syndrome (SLOS). In some embodiments, the disorder is desmosterolosis. In some embodiments, the disorder is sitosterolemia. In some embodiments, the disorder is cerebrotendinous xanthomatosis (CTX). In some embodiments, the disorder is mevalonate kinase deficiency (MKD). In some embodiments, the disorder is SC4MOL gene mutation (SMO deficiency). In some embodiments, the disorder is Niemann-Pick disease. In some embodiments, the disorder is autism spectrum disorder (ASD). In some embodiments, the disorder is associated with phenylketonuria.

[0111] Exemplary conditions associated with NMDA modulation include gastrointestinal (GI) disorders, e.g., constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) (e.g., ulcerative colitis, Crohn's disease), structural disorders affecting the GI, anal disorders (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, anal Examples of conditions that may be treated include, but are not limited to, peri-anal abscesses, anal fistulas), colon polyps, cancer, colitis and CNS conditions, such as those described herein.

[0112] Exemplary CNS conditions associated with NMDA modulation include adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, social phobia, generalized anxiety disorder), cognitive disorders (including Alzheimer's disease and other forms of dementia (e.g., frontotemporal dementia)), dissociative disorders, eating disorders, mood disorders (including depression (e.g., postpartum depression), bipolar disorder, dysthymic disorder, suicidal ideation), schizophrenia or other psychotic disorders (including schizoaffective disorder), sleep disorders (including insomnia), substance abuse-related disorders, personality disorders (including obsessive-compulsive personality disorder), These include, but are not limited to, autism spectrum disorders (including those with mutations in the Shank family of proteins (e.g., Shank3)), neurodevelopmental disorders (including Rett syndrome), multiple sclerosis, sterol synthesis disorders, pain (including acute and chronic pain; headaches, e.g., migraines), seizure disorders (including status epilepticus and monogenic forms of epilepsy, e.g., Dravet's disease and tuberous sclerosis syndrome (TSC)), stroke, traumatic brain injury, movement disorders (including Huntington's disease and Parkinson's disease) and tinnitus. In certain embodiments, the compounds of the present invention, e.g., compounds of formula (I) and pharmacologic salts thereof, may be used to induce sedation or anesthesia. In certain embodiments, the compounds described herein (e.g., compounds of Formula (I) and pharma- ceutically acceptable salts thereof) are useful in the treatment or prevention of adjustment disorders, anxiety disorders, cognitive disorders, dissociative disorders, eating disorders, mood disorders, schizophrenia or other psychotic disorders, sleep disorders, substance-related disorders, personality disorders, autism spectrum disorders, neurodevelopmental disorders, sterol synthesis disorders, pain, seizure disorders, stroke, traumatic brain injury, movement and visual disorders, hearing loss, and tinnitus. In some embodiments, the disorder is Huntington's disease. In some embodiments, the disorder is Parkinson's disease. In some embodiments, the disorder is an inflammatory disease (e.g., lupus).

[0113] In another aspect, there is provided a method of treating or preventing brain excitability in a subject susceptible to or afflicted with a condition associated with brain excitability, the method comprising administering to the subject an effective amount of a compound of the invention, e.g., a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0114] In yet another aspect, the present invention provides a combination of the compound of the present invention, for example, the compound of formula (I) or its pharma- ceutically acceptable salt, with another pharmacologically active agent.The compound provided herein can be administered as the only active agent, or can be administered in combination with other agents.The administration of the combination can proceed by any method obvious to those skilled in the art, including, for example, separate administration, sequential administration, simultaneous administration and alternating administration. Diseases and Disorders Methods for treating sterol synthesis disorders are described herein. Exemplary disorders are described herein. The methods include administering an NMDA receptor modulating compound to a subject, e.g., a subject suffering from a sterol synthesis disorder, such as SLOS. Exemplary compounds are described herein. Sterol synthesis disorder

[0115] In one aspect, a method for treating sterol synthesis disorders is described herein. Cholesterol has essential regulation in growth and development. Cholesterol is a membrane lipid and also a precursor of many molecules that play important roles in cell growth and differentiation, protein glycosylation and signal transduction pathways. Several enzymes and intermediates are involved in the biosynthesis of cholesterol. Disorders caused by deficiencies in any of the enzymes involved in cholesterol biosynthesis will result in the accumulation of intermediates and imbalance of biomolecules. This leads to disorders including congenital skeletal anomalies, dysmorphic facial features, psychomotor retardation and growth disorders. In certain embodiments, sterol synthesis disorders or symptoms of sterol synthesis disorders can be treated by administering a compound described herein (e.g., an NMDA receptor modulating compound as described herein) to a subject suffering from a sterol synthesis disorder. Additional disorders are described below. Smith-Lemli-Opitz syndrome

[0116] In one aspect, methods are described herein for treating Smith-Lemli-Opitz syndrome (or SLOS, or 7-dehydrocholesterol reductase deficiency). SLOS is an inborn error of cholesterol synthesis. In addition to microcephaly, moderate to severe intellectual disability, sensory hypersensitivity, stereotypic behavior, dysmorphic facial features, and syndactyly of the second / third toes, the disease is characterized by low levels of cerebrosterol (24(S)-hydroxycholesterol). SLOS is an autosomal recessive genetic condition resulting from a deficiency in the last enzyme in the cholesterol synthesis pathway, resulting in low or low-to-normal levels of plasma cholesterol and high levels of 7- and 8-dehydrocholesterol (DHC; 7DHC and 8DHC). Common treatments currently in use include dietary cholesterol supplementation, treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HMG CoA reductase inhibitors, also known as statins), and treatment with agents that increase cholesterol production and / or accumulation; and reducing the accumulation of the potentially toxic cholesterol precursors 7DHC and 8DHC. Desmosterolosis

[0117] Desmosterolosis is a deficiency of desmosterol reductase and has a similar phenotype to SLOS. In one aspect, described herein are methods for treating desmosterolosis with the compounds described herein. Sitosterolemia

[0118] Sitosterolemia is a rare autosomal recessive disorder caused by mutations in two ATP-binding cassette (ABC) transporter genes (ABCG5 and ABCG8). Sitosterolemia enhances the absorption of plant sterols and cholesterol from the intestine. Patients usually present with tendon and tuberous xanthomas and premature coronary artery disease. In one aspect, methods are described herein for treating sitosterolemia with the compounds described herein. Cerebrotendinous xanthomatosis (CTX)

[0119] In one aspect, described herein is a method for treating cerebrotendinous xanthomatosis (also called cerebral cholesterolosis or Van Bogaert-Scherer-Epstein syndrome) with the compounds described herein. CTX can be caused by a mutation in the CYP27A1 gene, which produces the sterol 27-hydroxylase enzyme. Sterol 27-hydroxylase metabolizes cholesterol into bile acids (e.g., chenodeoxycholic acid), which are important in the absorption of fat in the intestine. Malfunction of the enzyme can lead to cholesterol accumulation in tissues. CTX is characterized by diarrhea in children, cataracts in adults, tendon xanthomas, reduced mental capability, and abnormal movement. Mevalonate Kinase Deficiency Syndrome (MKD)

[0120] Mevalonate kinase deficiency (mevalonic aciduria, a more severe form of MKD) or hyperimmunoglobulin D syndrome with periodic fever syndrome (HIDS or hyperglobulin Demia, a more severe form of MKD) MKD, also called the more benign form, causes accumulation of mevalonic acid in the urine as a result of insufficient activity of mevalonate kinase. MKD can result in developmental delay, hypotonia, anemia, hepatosplenomegaly, dysmorphic features, mental retardation, and general growth retardation. Mevalonic aciduria is characterized by delayed physical and mental development, failure to thrive, recurrent episodes of fever accompanied by vomiting and diarrhea, enlarged liver, spleen, and lymph nodes, microcephaly (small head size), cataracts, hypotonia, short statute, distinctive facial features, ataxia, and anemia. HIDS is characterized by recurrent episodes of fever accompanied by enlarged lymph nodes, joint pain, gastrointestinal problems, and rash. In one aspect, methods are described herein for treating MKD with the compounds described herein. SC4MOL gene mutation (SMO deficiency)

[0121] SC4MOL gene deficiency is a genetic disorder in the cholesterol biosynthesis pathway (e.g., a mutation in the SC4MOL gene encoding a novel sterol oxidase). SC$MOL deficiency is characterized by the accumulation of dimethylsterols and monomethylsterols that can be detected in blood, skin slices, or primary skin fibroblasts. In one aspect, methods are described herein for treating SMO deficiency with the compounds described herein. Niemann-Pick disease

[0122] Niemann-Pick disease is a lysosomal storage disorder caused by a genetic mutation that affects metabolism. Niemann-Pick disease is caused by the body's inability to transport cholesterol and other fatty substances (lipids), leading to an abnormal buildup of these substances. This buildup is damaging to the affected area. autism

[0123] In one aspect, a method for treating autism spectrum disorder or autism is described herein. Autism spectrum disorder (ASD) and autism refer to a group of complex disorders of brain development. Autism is usually characterized by difficulties in social interaction, such as verbal and non-verbal communication. Individuals with autism often also exhibit repetitive behaviors. Autism may be accompanied by intellectual disability, motor coordination and attention difficulties, and physical health problems, such as sleep disorders and gastrointestinal disorders. Individuals with autism may also excel in visual skills, music, mathematics, and art. Autism may refer to autistic disorder, childhood disintegrative disorder, pervasive developmental disorder not otherwise specified (PDD-NOS) and Asperger's syndrome. Autism also refers to monogenic forms of autism, such as synaptophathy's, eg, Rett Syndrome, Fragile X Syndrome, and Angelman Syndrome. Phenylketonuria-related disorders

[0124] In one aspect, described herein is a method for treating disorders (e.g., cognitive disorders) associated with phenylketonuria with the compounds described herein. Phenylketonuria can lead to hypocholesterolemia and hypovitaminosis D states. Total and low-density cholesterol, as well as 25-hydroxyvitamin D, were found to be decreased in subjects with phenylketonuria compared to subjects without phenylketonuria (Clin. Chim. Acta 2013, 416:54-59). 24S-hydroxycholesterol and 27S-hydroxycholesterol and 7α-hydroxycholesterol (e.g., representative of peripheral and hepatic cholesterol excretion, respectively) were shown to be significantly decreased in subjects with phenylketonuria, while 7β-hydroxycholesterol (e.g., reflecting oxidative stress) was significantly increased in subjects with phenylketonuria. 24S-OHC and 7β-hydroxycholesterol Changes in the levels of 27S-hydroxycholesterol can be correlated with the levels of phenylalanine, and the levels of 27S-hydroxycholesterol can be correlated with the levels of 25-hydroxyvitamin D in subjects with phenylketonuria. EXAMPLES

[0125] In order that the invention described herein may be more fully understood, the following examples are set forth. Synthetic methods or intermediates may be used as described, for example, in WO2014 / 160480 * The synthetic and biological examples described herein are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and are not to be construed in any way as limiting the scope thereof.

[0126] The stereochemistry assigned herein (e.g., the assignment of "R" or "S" to the C24 position of a steroid) may be tentatively (e.g., randomly) assigned. For example, the C24 position may be depicted in the "R" configuration when the absolute configuration is "S". Also, the C24 position may be depicted in the "S" configuration when the absolute configuration is "R".

[0127] List of abbreviations Me: methyl;Ac: acetyl;Bu: butyl;t-Bu: tert-butyl;Ph: phenyl;THF: tetrahydrofuran;Na2SO4: sodium sulfate;NaHCO3: sodium bicarbonate;Na2S2O3: sodium thiosulfate;PE: petroleum ether;DCM: dichloromethane;DMF: N,N-dimethylformamide;Et: ethyl;EtOAc: ethyl acetate;EtOH: ethanol;MeOH: methyl alcohol;t-BuLi: tert-butyl lithium;MTBE: methyl tert-butyl ether;HMPA: hexamethylphosphoric triamide;n-BuLi: n-butyl lithium;TsCl: 4-methylbenzene-1-sulfonyl chloride;Ph3PMeBr: methyltriphenylphosphonium bromide;PCC: pyridyl chlorochromate dinium; t-BuOK: potassium tert-butoxide; TBAF: tetra-n-butylammonium fluoride; TBSCl: tert-butyl(chloro)dimethylsilane; AlMe3: trimethylaluminum; DMP: Dess-Martin periodinane; (i-PrO)4Ti: titanium tetraisopropoxide; LAH: lithium aluminum hydride; LDA: lithium diisopropylamide; MAD: methylaluminum bis(2,6-di-t-butyl-4-methylphenoxide); n-BuLi: normal-butyllithium; BHT: 2,6-di-t-butyl-p-cresol (butylated hydroxytoluene); DIEA: diisopropylethylamine; NCS: N-chlorosuccinimide; iPrMgBr: isopropylmagnesium bromide.

[0128] Synthesis method

[0129] Example 1. Synthesis of Compound 1 [ka] [ka] Step 1. Synthesis of intermediate A-1. To a suspension of PPh3MeBr (2.13 kg, 5.97 mol) in THF (3000 mL) was added t-BuOK (688 g, 6.14 mol) at 20° C. The suspension became yellow in color. After stirring at 50° C. for 1 h, pregnenolone (630 g, 2.05 mol) was added at 50° C. The reaction mixture was stirred at 50° C. for 2 h. After cooling to 20° C., the mixture was treated with NH4Cl (10% aqueous solution, 5 L) and heptane (3.5 L) and stirred for 15 min. The organic layer was separated and concentrated in vacuo to give the crude material as a thick oil, which was poured into MTBE (10 L) with vigorous stirring, and the mixture was stirred at room temperature for 16 h. An off-white solid formed, which was collected by filtration and washed with MTBE (3 L). The combined filtrates were mixed with MeOH (10 L) and concentrated in vacuo to 6 L. An off-white solid formed which was collected by filtration, washed with MeOH (3 L) and air-dried to give 700 g of a damp off-white solid. The combined MeOH filtrates were concentrated in vacuo to give a thick oil. The oil was poured into MTBE (3 L) with vigorous stirring and the mixture was stirred for 3 h. An off-white solid formed which was collected by filtration and washed with MTBE (1 L). The combined filtrates were mixed with MeOH (3 L) and concentrated in vacuo to 1.5 L. An off-white solid formed which was collected by filtration, washed with MeOH (500 mL) and air-dried to give 150 g of a damp off-white solid. The previous 700 g and 150 g batches were combined and dried in vacuo to give A-1 (552 g, 88%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 5.40-5.30 (m, 1H), 4.85 (s, 1H), 4.71 (s, 1H), 3.60-3.50 (m, 1H), 2.36-2.18 (m, 2H), 2.08-1.96 (m, 2H), 1.92-1.78 (m, 3H), 1.76 (s, 3H), 1.73-1.48 (m, 9H), 1.38-1.03 (m, 4H), 1.01 (s, 3H), 1.00-0.91 (m, 1H), 0.58 (s, 3H). Step 2. Synthesis of intermediate A-2. To a solution of A-1 (184 g, 585 mmol) in DCM (2000 mL) was added DMP (496 g, 1.17 mol) in small portions at 25° C. After addition of 100 mL of 1,000 ml of water (42 mL) was added. The mixture was stirred at 25° C. for 30 min, and water (1500 mL) and NaHCO3 (750 g) were added in small portions resulting in gas evolution. The mixture was then filtered through a pad of Celite and the solid was washed with DCM (500 mL). The organic layer of the filtrate was separated, washed with Na2S2O3 (1000 mL, saturated), dried over Na2SO4, filtered and concentrated in vacuo below 30° C. to give a pale yellow gum of A-2 (250 g, crude). The crude product was used directly in the next step. Step 3. Synthesis of intermediate A-3. To a solution of BHT (769 g, 3.49 mol) in toluene (1500 mL) was added AlMe3 (870 mL, 2 M in toluene, 1.74 mol) at 0° C. After stirring at 0° C. for 1 h, the reaction mixture was cooled to −78° C. and a solution of A-2 (250 g crude, theoretical mass: 182 g, 582 mmol) in toluene (1000 mL) was added. After stirring at −78° C. for 1 h, MeMgBr (580 mL, 3 M in ether, 1.74 mmol) was added at −78° C. and the mixture was stirred at −78° C. for another 1 h. The mixture was quenched by pouring in portions into citric acid (4000 mL, 20% aqueous solution), which released gas. Two other batches were performed and combined. The mixture was extracted with EtOAc (10 L). The organic layer was separated, washed with brine (5 L, 10%), NaHCO3 (5 L, sat. aq.), brine (5 L, sat.), dried over Na2SO4, and concentrated in vacuum. The crude product was purified by silica gel column (eluted with EtOAc from PE) to give crude A-3 (440 g) as a pale yellow solid. To a solution of crude A-3 (440 g) in DCM (6 L) was added DMAP (24.4 g) and Ac2O (51 g). The mixture was stirred at 20 °C for 1 h. To the mixture was added NaHCO3 (1 L, sat. aq.) and stirred for 10 min. The organic layer was separated, concentrated in vacuum, and the residue was triturated with PE (2 L). The solid was washed with PE (3 x 500 mL) and dried in vacuum to give A-3 (262 g) as an off-white solid. The combined filtrate was concentrated, purified by silica gel column (PE / EtOAc=50 / 1 to 8 / 1), and triturated with PE (1 L) to give A-3 (30 g). 1 H NMR (400 MHz, CDCl3) δ 5.35-5.28 (m, 1H), 4.85 (s, 1H), 4.71 (s, 1H), 2.48-2.37 (m, 1H), 2.08-1.94 (m, 3H), 1.92-1.85 (m, 1H), 1.82-1.33 (m, 14H), 1.29-1.08 (m, 7H), 1.02 (s, 3H), 1.00-0.93 (m, 1H), 0.59 (s, 3H). Step 4. Synthesis of intermediate A-4. A-3 (100 g, 304 mmol) was dissolved in 9-BBN (1.21 L, 0.5 M in THF, 608 mmol) at 0° C. under N2. The solution was stirred at 65° C. for 1 h and recooled to 10° C. An off-white solid precipitated. Ethanol (279 g, 6080 mmol) and aqueous NaOH (304 mL, 5 M, 1520 mmol) were added dropwise to the mixture below 10° C. to obtain a clear solution. Hydrogen peroxide (343 g, 30% aqueous solution, 3040 mmol) was then added dropwise below 10° C. The reaction mixture was stirred at 75° C. for 1 h. After recooling to 20° C., a white solid precipitated and was collected by filtration. The filter cake was washed with water (3×500 mL) and dried in vacuo to give a white solid, which was triturated in ethanol (1.5 L) at reflux to give A-4 (92 g, 88%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 5.31-5.29 (m, 1H), 3.65-3.63 (m, 1H), 3.38-3.37 (m, 1H), 2.42 (d, J = 12.4, 1H), 2.05-1.92 (m, 3H), 1.88-1.63 (m, 4H), 1.63-1.40 (m, 8H), 1.40-0.90 (m, 16H), 0.70 (s, 3H). Step 5. Synthesis of intermediate A-5. To a solution of A-4 (124.5 g, 357 mmol) in chloroform (1 L) and pyridine (700 mL) was added TsCl (204 g, 1071 mmol) at 15° C. The mixture was stirred at 15° C. for 2 h. The mixture was concentrated in vacuum to remove most of the chloroform. The pyridine mixture was added to water (6 L). An off-white solid formed, which was collected by filtration and washed with water (6×1 L). The off-white solid was dissolved in DCM (3.5 L), dried over Na2SO4, filtered, and concentrated in vacuum to give A-5 (163 g, 92%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 5.29-5.28 (m, 1H), 3.96 (dd, J = 3.2, 9.6 Hz, 1H), 3.79 (dd, J = 6.4, 9.2 Hz, 1H), 2.45 (s, 3H), 2.41 (d, J = 13.6 Hz, 1H), 1.99-1.91 (m, 3H), 1.77-1.39 (m, 11H), 1.26-0.86 (m, 16H), 0.64 (s, 3H). Step 6. Synthesis of compound A-6. To a solution of A-5 (163 g, 325 mmol) in DMF (1.7 L), KI (258 g, 1560 mmol) was added at 15° C., and the mixture was stirred at 60° C. for 2 h. Sodium benzenesulfinate (195 g, 975 mmol) was added, and the mixture was stirred at 60° C. for 2 h. The reaction mixture was cooled to 25° C. and combined with another batch of 83 g from A-5. The combined mixture was poured into water (20 L), which produced some yellow solid. The mixture was filtered, and the filter cake was washed with water (3×2 L). The resulting filter cake was dissolved in DCM (5 L), washed with water (2×1 L), brine (2×1 L), dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product as a yellow solid, which was recrystallized in toluene (2.5 L) to give A-6 (150 g, 65%) as a pale yellow solid. The recrystallized filtrate was concentrated in vacuo to give additional crude A-6 (30 g) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 7.2 Hz, 2H), 7.69-7.61 (m, 1H), 7.60-7.50 (m, 2H), 5.28-5.27 (m, 1H), 3.14 (d, J = 14.0 Hz, 1H), 2.85 (dd, J = 9.6, 14.0 Hz, 1H), 2.41 (d, J = 12.8 Hz, 1H), 2.17-2.03 (m, 1H), 2.02-1.87 (m, 3H), 1.81-1.65 (m, 3H), 1.60-1.32 (m, 8H), 1.25-0.85 (m, 15H), 0.65 (s, 3H). LCMS Rt = 2.057 min (3.0 min chromatography, 3 0-90AB), C 29 H 41 O2S[M+H-H2O] + MS ESI calculated value 453, measured value 453. Step 7. Synthesis of compound 1-2. To THF (2 mL) at -70°C under N2, n-BuLi (1.69 mL, 4.24 mmol) was added, and a suspension of A-6 (500 mg, 1.06 mmol) in THF (5 mL) was added dropwise to give a pale yellow suspension. After stirring at -70°C for 30 min, a solution of compound 1-1 (212 mg, 2.12 mmol) in THF (2 mL) was added. The reaction was stirred at -70°C for 10 min and at 25°C for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column (PE / EtOAc=10 / 1) to give compound 1-2 (500 mg, crude) as a yellow solid, which was used directly. Step 8. Synthesis of compound 1. To a solution of compound 1-2 (500 mg, 0.876 mmol) in MeOH (10 mL) was added Mg powder (630 mg, 26.3 mmol) at 60° C. The mixture was stirred at 60° C. for 2 h, and another batch of Mg powder (630 mg, 26.3 mmol) was added. The reaction was stirred at 60° C. for another 16 h. After cooling, the mixture was quenched with HCl (100 mL, 1 M) until the reaction was clear and extracted with DCM (2×30 mL). The combined organic phase was dried over Na2SO4, filtered, concentrated, and purified by silica gel column (PE / EtOAc=10 / 1 to 8 / 1) to give compound 1 (104 mg, 28%) as an off-white solid. Compound 1:1 H NMR (400 MHz, CDCl3) δ 5.31-5.30 (m, 1H), 3.19-3.05 (m, 1H), 2.44-2.40 (m, 1H), 2.08-1.91 (m, 3H), 1.91-1.57 (m, 6H), 1.52-1.35 (m, 11H), 1.74-1.12 (m, 10H), 1.11-1.01 (m, 5H), 0.90 (s, 9H), 0.68 (s, 3H). LCMS Rt=1.564 min (2 min chromatography, 10-80AB), C 29 H 47 [M+H-2H2O] + MS ESI calculated value 395, found value 395. Step 9. Compound 1 (0.83 g) was purified by SFC (column: AD (250 mm) * 30 mm, 5 um), 0.1% NH3H2O ​​ETOH, gradient: 30% to 100%, flow rate (ml / min): 60 mL / min, 25 °C) to give compound 1-A (379 mg, 46%) and compound 1-B (338 mg, 41%) as off-white solids. Compound 1-A: 1 H NMR (400 MHz, CDCl3) δ 5.33-5.28 (m, 1H), 3.12-3.06 (m, 1H), 2.45-2.40 (m, 1H), 2.05-1.92 (m, 3H), 1.91-1.64 (m, 5H), 1.63-1.57 (m, 3H), 1.52-1.38 (m, 6H), 1.37-1.24 (m, 3H), 1.21-1.09 (m, 5H), 1.09-1.03 (m, 2H), 1.02-1.00 (m, 4H), 0.99-0.96 (m, 1H), 0.94 (d, J = 6.8 Hz, 3H), 0.90 (s, 9H), 0.68 (s, 3H). LCMS Rt=1 .361 min (2.0 min chromatography, 30-90AB), C 29 H 47 [M+H-2H2O] +MS ESI calculated value 395, found value 395. Compound 1-B: 1 H NMR (400 MHz, CDCl3) δ 5.32-5.30 (m, 1H), 3.16-3.14 (m, 1H), 2.45-2.40 (m, 1H), 2.05-1.92 (m, 3H), 1.90-1.66 (m, 4H), 1.63-1.57 (m, 2H), 1.52-1.38 (m, 6H), 1.37-1.24 (m, 5H), 1.21-1.09 (m, 5H), 1.09-0.95 (m, 5H), 0.94 (d, J = 6.4 Hz, 3H), 0.90 (s, 9H), 0.69 (s, 3H). LCMS Rt = 1.361 min (2.0 min chromatography, 30-90AB), C 29 H 47 [M+H-2H2O] + MS ESI calculated value 395, found value 395. Example 2. Synthesis of Compound 2 [ka] Synthesis of compound 2-2. To THF (6 mL), n-BuLi (2.5 M, 2.65 mmol, 1.05 mL, 2.5 equiv) was added at −70° C. under N2, and a suspension of A-6 (1.06 mmol, 500 mg, 1.0 equiv) in THF (3 mL) was added dropwise to give a pale yellow suspension. After stirring at −70° C. for 30 min, a solution of compound 2-1 (1.27 mmol, 127 mg, 1.2 equiv) in THF (1 mL) was added dropwise. The reaction was stirred at 15° C. for 12 h. The reaction was quenched with saturated NH4Cl (30 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give compound 2-2 (560 mg, crude) as a pale yellow foam, which was used directly in the next step. Synthesis of compound 2. To a solution of compound 2-2 (560 mg, 0.98 mmol) in MeOH (10 mL) was added NiCl2 (127 mg, 0.980 mmol). After heating to 55 °C, Mg turnings (938 mg) were added and the mixture was stirred at 55 °C for 30 min. Then, another batch of Mg turnings (938 mg) was added and the reaction was stirred at 55 °C for 16 h. After cooling, the mixture was quenched with HCl (100 mL, 1N) until the reaction was clear and extracted with DCM (2 × 30 mL). The combined organic phase was dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column (0-10% EtOAc in PE / DCM (v / v = 2 / 1)) to give compound 2 (26 mg, 6%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 5.30-5.29 (m, 1H), 3.54-3.52 (m, 1H), 2.44-2.40 (m, 1H), 2.05-1.90 (m, 3H), 1.85-1.58 (m, 4H), 1.56-1.24 (m, 18H), 1.23-0.92 (m, 19H), 0.68 (s, 3H). LCMS Rt=1.359 min (2.0 min chromatography, 30-90AB_ELSD), C 29 H 47 [M+H-2H2O] + MS ESI calculated value 395, found value 395. Example 3. Synthesis of Compounds 3 and 4 [ka] Synthesis of compound 3-2. Compound 3-1 in THF (70 mL) *To a solution of (7.0 g, 16.2 mmol), ethylmagnesium bromide (26.9 mL, 80.9 mmol, 3M in Et2O) was added dropwise at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at 25° C. for 12 h. The mixture was quenched with saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (2×200 mL). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE / EtOAc=20 / 1) to give compound 3-2 (500 mg, 8%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 5.30-5.28 (m, 1H), 2.42-2.39 (m, 5H), 1.98-1.63 (m, 8H), 1.53-0.84 (m, 27H), 0.66 (s, 3H). Synthesis of compound 3-3. To a solution of compound 3-2 (500 mg, 1.24 mmol) in MeOH (10 mL) was added NaBH4 (93.8 mg, 2.48 mmol) in small portions. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (2 x 30 mL). The combined organic phase was washed with brine (30 mL) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE / EtOAc = 20 / 1) to give compound 3-3 (500 mg, crude), which was purified by preparative HPLC to give compound 3-3 (60 mg, 12%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 5.33-5.28 (m, 1H), 3.48-3.47 (m, 1H), 2.45-2.38 (m, 1H), 2.02-1.57 (m, 14H), 1.57-0.92 (m, 26H), 0.67 (s, 3H). Synthesis of compounds 3 and 4. Compound 3-3 (60 mg, 149 μmol) in MeOH (5 mL) was purified by SFC (column: AD (250 mm *Conditions: base-EtOH) to give peak 1 as compound 3 (33.6 mg, 56%) and peak 2 as compound 4 (18.3 mg, 31%) as off-white solids. Compound 3: 1 H NMR (400 MHz, CDCl3) δ 5.32-5.28 (m, 1H), 3.48-3.46 (m, 1H), 2.46-2.39 (m, 1H), 2.02-1.57 (m, 11H), 1.54-0.92 (m, 29H), 0.67 (s, 3H). LCMS Rt=1.443 min (2.0 min chromatography, 10-80AB), C 27 H 45 O[M-H2O+H] + MS ESI calculated value 385, found value 385. Compound 4: 1 H NMR (400 MHz, CDCl3) δ 5.33-.28 (m, 1H), 3.48-3.46 (m, 1H), 2.45-2.41 (m, 1H), 2.02-1.57 (m, 11H), 1.54-0.92 (m, 29H), 0.68 (s, 3H). LCMS Rt = 1.446 min (2.0 min chromatography, 1 0-80AB), C 27 H 45 O[M-H2O+H] + MS ESI calculated 385, found 385. Example 4. Synthesis of Compounds 6 and 7 [ka] To a solution of compound 3 (90 mg, 223 μmol) in EtOAc (10 mL) was added Pd / C (100 mg, 10%, dry), and then the mixture was stirred under hydrogen (50 psi) at 50° C. for 12 h. The mixture was filtered through a Celite pad, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc=20 / 1 to 10 / 1) to give compound 6 (4.8 mg, 5%) and compound 7 (44.5 mg, 49%) as off-white solids. Compound 6:1 H NMR (400 MHz, CDCl3) δ 3.47-3.46 (m, 1H), 2.05-1.82 (m, 4H), 1.79-1.57 (m, 2H), 1.55-0.90 (m, 38H), 0.64 (s, 3H).LCMS Rt = 1.484 min (2.0 min chromatography, 10-80AB), C 27 H 45 [M-2H2O+H] + MS ESI calculated value 369, found value 369. Compound 7: 1 H NMR (400 MHz, CDCl3) δ 3.49-3.46 (m, 1H), 1.97-1.90 (m, 1H), 1.90-1.55 (m, 1H), 1.55-1.62 (m, 4H), 1.53-1.24 (m, 19H), 1.23-0.82 (m, 15H), 0.80 (s, 3H), 0.64-0.63 (m, 4H). LCMS Rt=1.474 min (2.0 min chromatography, 10-80AB), C 27 H 45 [M-2H2O+H] + MS ESI calculated value 369, actual value 369. Example 5. Synthesis of Compounds 8 and 9 [ka] To a solution of compound 4 (90 mg, 223 umol) in EtOAc (10 mL), Pd / C (100 mg, 10%, dry) was added, and then the mixture was stirred under hydrogen (50 psi) at 50° C. for 12 h. The mixture was filtered through a Celite pad, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc=20 / 1 to 10 / 1) to give compound 8 (5.5 mg, 6%) and compound 9 (64.7 mg, 72%) as off-white solids. Compound 8: 1 H NMR (400 MHz, CDCl3) δ 3.47-3.46 (m, 1H), 1.86-1.75 (m, 4H), 1.65-0.90 (m, 40H), 0.64 (s, 3H). LCMS Rt=1.484 min (2.0 min chroma tography, 10-80AB), C 27 H 45 [M-2H2O+H] + MS ESI calculated value 369, found value 369. Compound 9: 1 H NMR (400 MHz, CDCl3) δ 3.47-3.46 (m, 1H), 1.97-1.90 (m, 1H), 1.90-1.78 (m, 1H), 1.70-1.58 (m, 6H), 1.50-0.90 (m, 35H), 0.64-0.63 (m, 4H). LCMS Rt=1.472 min (2.0 min chromatography, 10-80AB), C 27 H 45 [M-2H2O+H] + MS ESI calculated value 369, found value 369. Example 6. Synthesis of Compounds 10 and 11 [ka] Synthesis of compound 6-2. Compound 6-1 in THF (50 mL) * To a solution of (3.6 g, 8.07 mmol), isopropylmagnesium bromide (16.1 mL, 32.2 mmol, 2 M in THF) was added dropwise at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at 25° C. for 12 h. The mixture was quenched with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (2×100 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated in vacuum. The residue was purified by column chromatography on silica gel (PE / EtOAc=20 / 1) to give compound 6-2 (600 mg, 17%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 5.30-5.26 (m, 1H), 2.61-2.51 (m, 1H), 2.38-2.34 (m, 3H), 2.01-1.59 (m, 8H), 1.55-1.25 (m, 11H), 1.23-0.83 (m, 21H), 0.67 (s, 3H) . Synthesis of compound 6-3. To a suspension of compound 6-2 (500 mg, 1.16 mmol) in MeOH (8 mL) was added NaBH4 (87.7 mg, 2.32 mmol) in small portions. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with saturated aqueous NH4Cl (10 mL) and H2O (30 mL) was added. An off-white solid precipitated, was filtered, collected, and dried in vacuum to give compound 6-3 (500 mg, 100%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 5.30-5.26 (m,1H), 3.31-3.30 (m, 1H), 2.40-2.30 (m, 1H), 2.04-1.63 (m, 7H), 1.55-1.25 (m, 15H), 1.23-0.84 (m, 22H), 0.67 (s, 3H). Synthesis of compounds 10 and 11. Compound 6-3 (500 mg, 1.16 mmol) in MeOH (10 mL) was subjected to SFC under basic conditions (column: AD (250 mm * 30 mm, 5 um; Conditions: base-MeOH) to give peak 1 as compound 10 and peak 2 as compound 11 (230 mg, 46%) as off-white solids. Compound 10: 1 H NMR (400 MHz, CDCl3) δ 5.30-5.24 (m, 1H), 3.32-3.31 (m, 1H), 2.40-2.34 (m, 1H), 2.04-1.90 (m, 3H), 1.90-1.57 (m, 10H), 1.55-1.25 (m, 9H), 1.23-0.82 (m, 22H), 0.67 (s, 3H). LCMS Rt=1.648 min (2.0 min chromatography, 10-80AB), C 29 H 49 O[M-H2O+H] + MS ESI calculated value 413, found value 413. Compound 11: 1 H NMR (400 MHz, CDCl3) δ 5.29-5.25 (m, 1H), 3.32-3.31 (m, 1H), 2.40-2.32 (m, 1H), 2.04-1.57 (m, 6H), 1.54-1.25 (m, 17H), 1.23-0.84 (m, 21H), 0.68 (s, 3H) LCMS Rt=1.641 min (2.0 min chromatography, 10-80AB), C 29 H 49 O[M-H2O+H] + MS ESI calculated value 413, measured value 413. Example 7. Synthesis of Compounds 12 and 13 [ka] To a solution of compound 10 (150 mg, 348 μmol) in EtOAc (15 mL) was added Pd / C (200 mg, 10%, dry), and then the mixture was stirred under hydrogen (50 psi) at 50° C. for 12 h. The mixture was filtered through a Celite pad, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc=30 / 1 to 20 / 1) to give compound 12 (10.8 mg, 7%) and compound 13 (82.7 mg, 55%) as off-white solids. Compound 12: 1 H NMR (400 MHz, CDCl3) δ 3.31-3.30 (m, 1H), 1.95-1.58 (m, 5H), 1.50-1.10 (m, 22H), 1.10-0.88 (m, 21H), 0.64 (s, 3H). LCMS Rt=1.680 min (2.0 min chromatography, 10-80AB), C 29 H 49 [M-2H2O+H] + MS ESI calculated value 397, found value 397. Compound 13: 1 H NMR (400 MHz, CDCl3) δ 3.31-3.30 (m, 1H), 1.97-1.80 (m, 1H), 1.80-1.75 (m, 1H), 1.75-1.58 (m, 4H), 1.58-1.25 (m, 17H), 1.25-0.82 (m, 24H), 0.64-0.63 (m, 4H). LCMS Rt=1.682 min (2.0 min chromatography, 10-80AB), C 29 H 49 [M-2H2O+H] + MS ESI calculated value 397, found value 397. Example 8. Synthesis of Compounds 14 and 15 [ka] To a solution of compound 11 (150 mg, 348 μmol) in EtOAc (15 mL) was added Pd / C (200 mg, 10%, dry), and then the mixture was stirred under hydrogen (50 psi) at 50° C. for 12 h. The mixture was filtered through a Celite pad, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc=30 / 1 to 20 / 1) to give compound 14 (10.1 mg, 7%) and compound 15 (65.8 mg, 44%) as off-white solids. Compound 14: 1 H NMR (400 MHz, CDCl3) δ 3.31-3.30 (m, 1H), 1.95-1.57 (m, 7H), 1.50-1.10 (m, 22H), 1.10-0.90 (m, 19H), 0.65 (s, 3H). LCMS Rt=1.702 min (2.0 min chromatography, 10-80AB), C 29 H 49 [M-2H2O+H] + MS ESI calculated value 397, found value 397. Compound 15: 1H NMR (400 MHz, CDCl3) δ 3.31-3.30 (m, 1H), 1.95-1.90 (m, 1H), 1.90-1.76 (m, 1H), 1.76-1.57 (m, 4H), 1.5.57-1.25 (m, 18H), 1.25-0.70 (m, 23H), 0.64-0.63 (m, 4H). LCMS Rt=1.686 min (2.0 min Chromatography, 10-80AB), C 29 H 49 [M-2H2O+H] + MS ESI calculated value 397, actual value 397. Example 9. Synthesis of Compounds 16 and 17 [ka] Synthesis of compound 9-2. To a solution of 2,6-di-tert-butyl-4-methylphenol (220 g, 1.0 mol) in toluene (250 mL), AlMe3 (250 mL, 501 mmol, 2 M in toluene) was added dropwise at less than 25° C. The solution was stirred at 25° C. for 1 h. Then, a solution of compound 9-1 (50 g, 167 mmol) in DCM (400 mL) was added dropwise at −78° C. After stirring at −78° C. for 1 h, EtMgBr (167 mL, 501 mmol, 3 M in ethyl ether) was added dropwise at −78° C. The resulting solution was stirred at −78° C. to −50° C. for 3 h. The reaction was quenched with saturated citric acid (100 mL) at −78° C. After stirring at 25° C. for 0.5 h, the resulting mixture was filtered and the filtrate was extracted with DCM (3×100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. This reaction was run twice in parallel. The crude products were combined and purified by silica gel column (PE / EtOAc=5 / 1) to give 38 g of crude product as a white solid, which was recrystallized from PE to give compound 9-2 as an off-white solid (13.5 g, 13%). 1 H NMR (CDCl3) 400MHz δ 5.33-5.26 (m, 1H), 5.23-5.10 (m, 1H), 2.45-1.90 (m, 6H), 1.78-0.70 (m, 28H). Synthesis of compound 9-3. To a solution of compound 9-2 (13 g, 39.5 mmol) and methyl propiolate (8.29 g, 98.7 mmol) in anhydrous DCM (100 mL) at 0° C. under N2, diethylaluminum chloride (1 M in hexane, 158 mL, 158 mmol) was added dropwise. The mixture was stirred at 20° C. for 16 h. The reaction mixture was poured into ice water and extracted with DCM (3×300 mL). The extract was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc=5 / 1) to give compound 9-3 (14 g, 86%) as an off-white solid. 1 H NMR (CDCl3) 400MHz δ 6.93 (dd, J = 15.6Hz, 8.0Hz, 1H), 5.81 (d, J = 8.0Hz, 1H), 5.42-5.38 (m, 1H), 5.33-5.24 (m, 1H), 3.73 (s, 3H), 3.05-2.95 (m, 1H), 2.40-2.30 (m, 1H), 2.10-1.95 (m, 3H), 1.90-1.65 (m, 4H), 1.60-1.25 (m, 9H), 1.88 (d, J = 7.2 Hz, 3H), 1.15-0.95 (m, 6H), 0.84 (t, J = 7.6Hz, 3H), 0.78 (s, 3H). Synthesis of compound 9-4. To a solution of compound 9-3 (9 g, 21.8 mmol) in THF (100 mL) was added Pd / C (2 g, 10% wet) at 15° C. After being degassed and backfilled with H2 three times, the reaction mixture was stirred at 15° C. with a H2 balloon for 16 h. The mixture was filtered through a Celite pad. The filtrate was concentrated in vacuo to give crude compound 9-4 (8.7 g, crude) as an off-white solid. 1H NMR (CDCl3) 400MHz δ 5.35-5.25 (m, 1H), 3.69 (s, 3H), 2.40-2.15 (m, 4H), 2.10-1.40 (m, 17H), 2.15-0.80 (m, 16H), 0.70 (s, 3H). Synthesis of compound 9-5. To a solution of compound 9-4 (5 g, 12.0 mmol) in THF (100 mL) was added lithium aluminum hydride (1.13 g, 30.0 mmol) at 0° C. The reaction was then stirred at 25° C. for 5 min. The reaction was then quenched with aqueous NH4Cl (50 mL) and aqueous citric acid (30 mL) to pH=4-5. The reaction solution was then extracted with EtOAc (3×100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give crude compound 9-5 (4 g, 80%) as an off-white solid. 1 H NMR (CDCl3) 400MHz δ 5.35-5.25 (m, 1H), 3.18-3.05 (m, 2H), 2.40-2.32 (m, 1H), 2.08-1.80 (m, 18H), 1.80-0.80 (m, 19H), 0.68 (s, 3H). Synthesis of compound 9-6. To a solution of compound 9-5 (1 g, 2.57 mmol) in DCM (15 mL) and THF (15 mL) was added PCC (1.10 g, 5.14 mmol). The resulting reaction mixture was stirred at 25 °C for 2 h. The combined organic phase was dried, concentrated and purified by Combiflash (0-15% EtOAc in PE) to give compound 9-6 (700 mg, 70%) as an off-white solid. 1 H NMR (CDCl3) 400MHz δ 9.77 (s, 1H), 5.30-5.26 (m, 1H), 2.46-2.35 (m, 2H), 2.04-1.57 (m, 12H), 1.50-0.83 (m, 23H), 0.68 (m, 3H). Synthesis of compound 9-7. To a solution of compound 9-6 (100 mg, 0.258 mmol) in THF (5 mL) was added methylmagnesium bromide (0.513 ml, 1.54 mmol) under N2. The resulting reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with saturated NH4Cl solution (10 mL) and then concentrated to give a residue, which was extracted with EtOAc (3 × 10 mL). The combined organic phase was dried, concentrated, and purified by CombiFlash (0-15% EtOAc in PE) to give compound 9-7 (10 mg, 10%) as an off-white solid. 1 H NMR (CDCl3) 400MHz δ 5.30-5.24 (m, 1H), 3.80-3.74 (m, 1H), 2.38-2.35 (m, 1H), 2.05-0.83 (m, 40H), 0.68 (m, 3H). 27 H 45 O[M-H2O+H] + LCMS MS ESI calculations Value 385, actual value 385. Synthesis of compounds 16 and 17. Compound 9-7 (150 mg, 0.372 mmol) was purified by SFC (column: AD (250 mm * 30 mm, 10 um), conditions: base-MEOH) to give compound 16 (10.6 mg, 7%) and compound 17 (25.2 mg, 17%) as off-white solids. Compound 16: 1 H NMR (400 MHz, CDCl3) δ 5.29-5.27 (m, 1H), 3.75-3.71 (m, 1H), 2.38-2.34 (m, 1H), 2.05-0.80 (m, 40H), 0.67 (s, 3H). LCMS t R = 1.221 min (2 min chromatography, 30-90AB_ELSD), C 27 H 45 O[M-H2O+H] + MS ESI calculated value 385, found value 385. Compound 17: 1H NMR (400 MHz, CDCl3) δ 5.29-5.27 (m, 1H), 3.75-3.71 (m, 1H), 2.38-2.34 (m, 1H), 2.05-0.80 (m, 40H), 0.67 (s, 3H). LCMS t R = 1.216 min (2 min chromatography, 30-90AB_ELSD), C 27 H 45 O[M-H2O+H] + MS ESI calculated value 385, measured value 385. Example 10. Synthesis of Compounds 18 and 19 [ka] Synthesis of compound 10-2. Compound 10-1 in THF (30 mL) * A solution of (2 g, 5.01 mmol) and Pd / C (200 mg, 10%) was hydrogenated under 15 psi of hydrogen for 3 h at 25° C. The mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo to give compound 10-2 (1.8 g, crude) as an off-white solid. Synthesis of compound 10-3. To a solution of compound 10-2 (1.8 g, 4.47 mmol) in THF (25 mL) was added a solution of LiAlH4 (339 mg, 8.94 mmol) in THF (5 mL) dropwise below 15 °C. The solution was stirred at 15 °C for 2 h. The reaction was quenched by adding saturated aqueous NH4Cl solution (20 mL) at 0 °C. The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (2 x 30 mL) and concentrated in vacuum to give compound 10-3 (1.6 g, crude) as a pale yellow solid. Synthesis of compound 10-4. A mixture of compound 10-3 (1.6 g, 4.27 mmol) in DCM (10 mL) and THF (10 mL) was added to PCC (2.27 g, 10.6 mmol) at 25° C. The reaction was stirred at 25° C. for 3 h. The solution was filtered and the filter cake was washed with DCM (25 mL). The combined filtrate was concentrated in vacuum. The residue was purified by silica gel column eluted with PE / EtOAc=8 / 1 to give compound 10-4 (0.9 g, 54%) as an off-white solid. Synthesis of compound 10-5. To a solution of compound 10-4 (0.9 g, 2.41 mmol) in THF (30 mL) was added isopropylmagnesium chloride (3.61 mL, 7.23 mmol, 2M in THF) dropwise at -78 °C. The mixture was stirred at -78 °C for 2 h. The mixture was then warmed to 25 °C and stirred for 3 h. The reaction was poured into water (100 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuum. The residue was purified by silica gel column eluted with PE / EtOAc = 5 / 1 to give compound 10-5 (0.6 g, 57%) as an off-white solid. Synthesis of compounds 18 and 19. Compound 10-5 (0.6 g) was subjected to SFC under basic conditions (column: AD (250 mm * 30 mm, 5 um; Conditions: base-MEOH) to give peak 1 as compound 18 (140 mg, 23%) as an off-white solid and peak 2 as compound 19 (220 mg, 37%) as a pale yellow solid. Compound 18: 1 H NMR (400 MHz, CDCl3) δ 5.35-5.27 (m, 1H), 3.38-3.26 (m, 1H), 2.52-2.37 (m, 1H), 2.07-1.92 (m, 3H), 1.90-1.59 (m, 6H), 1.56-1.35 (m, 7H), 1.33-1.21 (m, 3H), 1.18-1.10 (m, 7H), 1.03-1.00 (m, 6H), 0.97-0.87 (m, 10H), 0.68 (s, 3H).LCMS Rt = 1.298 minutes (2 minutes of chromatogram Raffi, 30-90AB), C 28 H 47 O[M-H2O+H] + MS ESI calculated value 399, found value 399. Compound 19: 1 H NMR (400 MHz, CDCl3) δ 5.33-5.25 (m, 1H), 3.30 (br. s., 1H), 2.41 (d, J=13.2 Hz, 1H), 2.05-1.90 (m, 3H), 1.90-1.55 (m, 6H), 1.51-1.04 (m, 19H), 1.03-0.96 (m, 4H), 0.95-0.85 (m, 10H), 0.67 (s, 3H). LCMS R t = 1.294 minutes (2 minutes of chromatography Graphy, 30-90AB), C 28 H 47 O[M-H2O+H] + MS ESI calculated value 399, found value 399. Example 11. Synthesis of Compound 20 [ka] A mixture of compound 18 (50 mg, 119 μmol) and Pd / C (50 mg, 10%) in EtOH (10 mL) was hydrogenated under H2 (50 psi) at 50°C for 12 h. The reaction mixture was filtered through a Celite pad and the pad was washed with EtOAc (2 x 20 mL). The combined filtrate was concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc = 20 / 1 to 10 / 1) to give compound 20 (38.5 mg, 76%) as an off-white powder. 1 H NMR (400 MHz, CDCl3) δ 3.31-3.30 (m, 1H), 1.96-1.90 (m, 1H), 1.90-1.75 (m, 1H), 1.75-1.57 (m, 4H), 1.54-0.80 (m, 39H), 0.65-064 (m, 4H). LCMS Rt=1.578 min (2.0 min chromatography, 10-80AB), C 28 H 47 [M-2H2O+H] + MS ESI calculated value 383, measured value 383. Example 12. Synthesis of Compound 21 [ka] A mixture of compound 19 (50 mg, 119 μmol) and Pd / C (50 mg, 10%) in EtOH (10 mL) was hydrogenated under H2 (50 psi) at 50°C for 12 h. The reaction mixture was filtered through a Celite pad and the pad was washed with EtOAc (20 mL x 2). The combined filtrate was concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc = 20 / 1 to 10 / 1) to give compound 21 (9.8 mg, 20%) as an off-white powder. 1 H NMR (400 MHz, CDCl3) δ 3.31-3.30 (m, 1H), 1.97-1.92 (m, 1H), 1.92-1.75 (m, 1H), 1.75-1.57 (m, 27H), 1.54-0.80 (m, 16H), 0.65-064 (m, 4H). LCMS Rt=1.535 min (2.0 min chromatography, 10-80AB), C 28 H 47 [M-2H2O+H] + MS ESI calculated value 383, measured value 383. Example 13. Synthesis of Compounds 22 and 23 [ka] Synthesis of compounds 22 and 23. To a solution of compound 9-6 (340 mg, 879 μmol) in THF (20 mL) at 0 °C was added ethylmagnesium bromide (876 μL, 3.0 M, 2.63 mmol) was added. The reaction mixture was stirred at 15° C. for 2 h, then quenched with saturated NH4Cl (10 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with brine (60 mL), dried over Na2SO4, filtered and concentrated in vacuo to give compound 13-1 as an off-white solid (240 mg). The solid was purified by SFC (column: AD (250 mm) chromatography). * 30 mm, 5 um); Conditions: base-MeOH) to give peak 1 as compound 22 (13 mg, 4%) as an off-white solid and peak 2 as compound 23 (54.0 mg, impure) as an off-white solid. Compound 22: 1 H NMR (400 MHz, CDCl3) δ 5.31 (d, J = 5.0 Hz, 1H), 3.49 (br. s., 1H), 2.39 (d, J = 11.0 Hz, 1H), 2.09-1.94 (m, 3H), 1.92-1.80 (m, 1H), 1.78-1.71 (m, 1H), 1.69-1.37 (m, 16H), 1.35-1.23 (m, 4H), 1.22-0.92 (m, 14H), 0.87 (t, J = 7.5 Hz, 3H), 0.70 (s, 3H). LCMS R t = 2.334 min (4 min chromatography, 50-100AB), C 28 H 47 O[[M-H2O+H] + MS ESI calculated value 399, found value 399. Further purification of compound 23. Compound 23 (54 mg, 129 μmol, impure) was purified by SFC (column: AD (250 mm * 30 mm, 5 um); Conditions: base-MEOH) to give a pale yellow solid (34 mg), which was further purified by trituration from n-hexane to give compound 23 (8.5 mg, 16%) as an off-white solid.1 H NMR (400 MHz, CDCl3) δ 5.32 (br. s., 1H), 3.51 (br. s., 1H), 2.39 (d, J = 13.1 Hz, 1H), 2.11-1.95 (m, 3H), 1.93-1.82 (m, 1H), 1.75 (d, J = 13.3 Hz, 1H), 1.69-1.35 (m, 18H), 1.33-1.24 (m, 3H), 1.23-0.91 (m, 13H), 0.87 (t, J = 7.4 Hz, 3H), 0.70 (s, 3H).LCMS R t = 2.340 min (4 min chromatography, 50- 100AB), C 28 H 47 O[[M-H2O+H] + MS ESI calculated value 399, found value 399. Example 14. Synthesis of Compounds 24, 25, and 26 [ka] Synthesis of compound 24: To a solution of compound 9-6 (0.7 g, 1.80 mmol) in THF (10 mL) was added cyclopropylmagnesium bromide (180 mL, 90 mmol, 0.5 M in THF) in small portions. The mixture was stirred at 15° C. for 16 h. The mixture was quenched with saturated NH4Cl solution (100 mL) and then extracted with EtOAc (2×30 mL). The combined organic phase was dried, concentrated, and purified by preparative HPLC to give compound 24 (50 mg, 6%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 5.29-5.27 (m, 1H), 2.81 (s, 1H), 2.38-2.34 (m, 1H), 2.05-0.85 (m, 38H), 0.67 (s, 3H), 0.60-0.45 (m, 2H), 0.30-0.15 (m, 2H). LCMS Rt=1.284 min (2 min chromatography, 30-90AB_ELSD), C 29 H 45 [M-2H2O+H] +MS ESI calculated value 393, found value 393. Synthesis of compounds 25 and 26: 90 mg of compound 24 (90 mg, 0.209 mmol) was mixed with SFC (column: AD (250 mm * 30 mm, 5 um; Conditions: base-MEOH) to give peak 1 as compound 25 (24.0 mg, 27%) and peak 26 as compound 26. (11.1 mg, 12%) of peak 2 was obtained as an off-white solid. Compound 25: 1 H NMR (400 MHz, CDCl3) δ 5.29-5.27 (m, 1H), 2.82-2.79 (m, 1H), 2.43-2.40 (m, 1H), 2.05-0.80 (m, 38H), 0.67 (s, 3H), 0.55-0.40 (m, 2H), 0.30-0.15 (m, 2H).LCMS t R = 1.280 min (2 min chromatography -, 30-90AB_ELSD), C 29 H 45 [M-2H2O+H] + MS ESI calculated value 393, found value 393. Compound 26: 1 H NMR (400 MHz, CDCl3) δ 5.29-5.27 (m, 1H), 2.82-2.79 (m, 1H), 2.43-2.40 (m, 1H), 2.05-0.80 (m, 38H), 0.67 (s, 3H), 0.55-0.40 (m, 2H), 0.30-0.15 (m, 2H). LCMS R t = 1.282 min (2 min chromatography, 30-90AB_ELSD), C 29 H 45 [M-2H2O+H] + MS ESI calculated value 393, found value 393. Example 15. Synthesis of Compounds 27, 28, and 29 [ka] To a solution of compound 10-4 (4 g, 10.7 mmol) in THF (50 mL) was added cyclopropylmagnesium bromide (428 mL, 214 mmol, 0.5 M in THF) in small portions. The mixture was stirred at 15° C. for 16 h. The mixture was quenched with saturated NH4Cl solution (500 mL) and then extracted with EtOAc (2×100 mL). The combined organic phases were dried, concentrated and purified by Combiflash (0-20% EtOAc in PE) to give compound 27 (2 g, 45%) as an off-white solid. Compound 27: 1 H NMR (400 MHz, CDCl3) δ 5.30-5.29 (m, 1H), 2.80 (s, 1H), 2.43-2.40 (m, 1H), 2.02-1.43 (m, 16H), 1.40-0.80 (m, 20H), 0.67 (s, 3H), 0.55-0.40 (m, 2H), 0.30-0.15 (m, 2H). LCMS Rt=1.23 1 min (2 min chromatography, 30-90AB_ELSD), C 28 H 43 [M-2H2O+H] + MS ESI calculated value 379, found value 379. Synthesis of compounds 28 and 29. 0.17 g of compound 27 (170 mg, 0.409 mmol) was mixed with SFC (column: AY (250 mm * Conditions: base-IPA) to give peak 1 as compound 28 (37 mg, 22%) and peak 2 as compound 29 (50 mg, 30%) as off-white solids. Compound 28: 1 H NMR (400 MHz, CDCl3) δ 5.30-5.29 (m, 1H), 2.82-2.79 (m, 1H), 2.43-2.40 (m, 1H), 2.05-0.80 (m, 36H), 0.67 (s, 3H), 0.55-0.40 (m, 2H), 0.30-0.15 (m, 2H).LCMS Rt=1.217 min (2 min chromatography, 3 0-90AB_ELSD), C 28 H 43[M-2H2O+H] + MS ESI calculated value 379, found value 379. Compound 29: 1 H NMR (400 MHz, CDCl3) δ 5.30-5.29 (m, 1H), 2.82-2.79 (m, 1H), 2.43-2.40 (m, 1H), 2.05-0.80 (m, 36H), 0.68 (s, 3H), 0.55-0.40 (m, 2H), 0.30-0.15 (m, 2H). LCMS Rt=1.2 18 min (2 min chromatography, 30-90AB_ELSD), C 28 H 43 [M-2H2O+H] + MS ESI calculated value 379, found value 379. Example 16. Synthesis of Compound 30 [ka] Synthesis of compound 16-2. To a solution of compound 16-1 (5 g, 12.8 mmol) in ethanol (100 mL) was added Pd / C (dried, 10% on carbon, 1 g). The mixture was degassed and purged with H2 three times and stirred at 50 psi at 50 °C for 16 h. The reaction mixture was filtered through a Celite pad and the filter cake was washed with DCM (100 mL). The filtrate was concentrated to give compound 16-2 (5 g, 100%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 3.66 (s, 3H), 3.63-3.53 (m, 1H), 2.41-2.29 (m, 1H), 2.26-2.16 (m, 1H), 1.98-1.89 (m, 1H), 1.86-1.55 (m, 6H), 1.51-1.17 (m, 12H), 1.15-0.95 (m, 5H), 0.94-0.82 (m, 5H), 0.79 (s, 3H), 0.67-0.56 (m, 4H). Synthesis of compound 16-3. To a solution of compound 16-2 (11 g, 28.1 mmol) in DCM (200 mL) was added silica gel (9 g) and PCC (9.07 g, 42.1 mmol). The mixture turned dark and was stirred at 15° C. for 16 h. The reaction mixture was filtered and the filtrate was concentrated. The dark residue was purified by column chromatography on silica gel (PE / EtOAc / DCM=15 / 1 / 1) to give compound 16-3 (10.5 g, 96%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 3.66 (s, 3H), 2.43-2.16 (m, 5H), 2.10-1.94 (m, 3H), 1.91-1.74 (m, 2H), 1.73-1.65 (m, 1H), 1.58-1.46 (m, 3H), 1.43-1.23 (m, 8H), 1.18-0.98 (m, 7H), 0.94-0.83 (m, 4H), 0.76-0.65 (m, 4H). LCMS Rt=1 .257 min (2 min chromatography, 30-90AB), C 25 H 41 O3 [M+H] + MS ESI calculated value 389, found value 389. Synthesis of compound 16-4. To a solution of 2,6-di-tert-butyl-4-methylphenol (20.41 g, 92.5 mmol) in anhydrous toluene (70 mL) at 0° C. under N2, trimethylaluminum (2 M in toluene, 23.1 mL, 46.2 mmol) was added dropwise. The mixture was stirred at 0° C. for 1 h and cooled to −70° C. To the above solution, a solution of compound 16-3 (6 g, 15.4 mmol) in anhydrous toluene (100 mL) was added dropwise. The mixture was stirred at −70° C. for 1 h, then methylmagnesium bromide (3 M in diethyl ether, 15.4 mL, 46.2 mmol) was added dropwise. The resulting mixture was stirred at −70° C. for 2 h. The reaction mixture was quenched with aqueous citric acid (200 mL) and extracted three times with EtOAc and THF (200 mL / 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc / THF=20 / 1 / 1) to give compound 16-4 (6 g, 96%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 3.66 (s, 3H), 2.40-2.16 (m, 2H), 1.99-1.90 (m, 1H), 1.89-1.73 (m, 2H), 1.68-0.83 (m, 29H), 0.80 (s, 3H), 0.70-0.60 (m, 4H). LCMS Rt=1.273 min (2 min chromatography, 30-90AB), C 26 H 43 O2 [M-H2O+H] + MS ESI calculated value 387, found value 387. Synthesis of compound 16-5. To a solution of compound 16-4 (3 g, 7.41 mmol) in anhydrous THF (50 mL) at 0 °C, LiAlH4 (421 mg, 11.1 mmol) was added in small portions. The mixture was stirred at 0 °C for 30 min. The reaction mixture was diluted with water (5 mL). The reaction was quenched by dropwise addition of aqueous NaOH (10%, 5 mL), then filtered through a pad of Celite. The filter cake was washed with THF (5×20 mL). The filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 16-5 (2.5 g, 90% yield) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 3.61 (s, 2H), 1.97-1.94 (m, 1H), 1.89-1.75 (m, 1H), 1.68-1.52 (m, 6H), 1.50-1.18 (m, 16H),1.17-0.84 (m, 11H), 0.80 (s, 3H), 0.70-0.60 (m, 4H).LCMS Rt = 1.137 min (2 min chromatography, 30-90AB), C 25 H 43 O[M-H2O+H] + MS ESI calculated value 359, found value 359. Synthesis of compound 16-6. To a solution of compound 16-5 (2 g, 5.31 mmol) in anhydrous DCM (30 mL) was added silica gel (2.5 g) and PCC (2.28 g, 10.6 mmol). The mixture was stirred at 15° C. for 16 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc / THF=20 / 1 / 1) to give compound 16-6 (1.3 g, 66%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 2.51-2.26 (m, 2H), 1.99-1.73 (m, 3H), 1.69-1.18 (m, 19H), 1.17-0.83 (m, 10H), 0.80 (s, 3H), 0.72-0.59 (m, 4H). LCMS Rt=1.212 min (2 min chromatography, 30-90AB), C 25 H 39 [M-2H2O+H-] + MS ESI calculated value 339, measured value 339. Synthesis of compound 30. To a solution of cyclopropylmagnesium bromide (0.5M in THF, 21.2 mL, 10.6 mmol) under N2 was added compound 16-6 (200 mg, 0.533 mmol) at 25 °C. The mixture was stirred at 50 °C for 16 h. The reaction mixture was quenched with aqueous NH4Cl (50 mL), extracted with EtOAc (3 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc = 20 / 1) to give compound 30 (100 mg, 45%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 2.85-2.75 (m, 1H), 2.00-1.93 (m, 1H), 1.93-1.73 (m, 1H), 1.73-0.83 (m, 34H), 0.80 (s, 3H), 0.70-0.59 (m, 4H), 0.57-0.43 (m, 2H), 0.30-0.16 (m, 2H). LCMS Rt=1.443 min (2 min chromatography, 10-80AB), C 28 H 45 [M-2H2O+H] + MS ESI calculated value 381, found value 381. Example 17. Synthesis of Compounds 31 and 32 [ka] Synthesis of compound 17-2. To a solution of compound 30 (440 mg, 1.05 mmol) in pyridine (10 mL) was added benzoyl chloride (295 mg, 2.10 mmol) at 25° C. The reaction was then stirred at 50° C. for 16 h. The reaction was quenched by the addition of water (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column (PE / EtOAC=40 / 1) to give compound 17-2 (420 mg, 64%) as a yellow oil. Synthesis of compounds 17-3 and 17-4. The mixture of compound 17-2 was separated by SFC (column :AD(250mm *The mixture was purified by a 30 mm, 10 um) gradient: B in A (A=NH3.H2O, B=EtOH), flow rate: 30 mL / min) to give peak 1 as compound 17-3 (170 mg, 41%) as an off-white solid, and peak 2 as compound 17-4 (160 mg, 38%) as an off-white solid. Compound 17-3: 1 H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.8Hz, 2H), 7.99 (d, J = 8.4Hz, 2H), 7.58-7.48 (m, 2H), 7.48-7.38 (m, 4H), 4.55-4.45 (m, 1H), 2.11-0.77 (m, 37H), 0.73-0.55 (m, 5H), 0.52-0.45 (m, 2H), 0.39-0.31 (m, 1H). Compound 17-3: 1 H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.8Hz, 2H), 7.99 (d, J = 8.4Hz, 2H), 7.58-7.48 (m, 2H), 7.48-7.38 (m, 4H), 4.55-4.45 (m, 1H), 2.11-0.77 (m, 37H), 0.73-0.55 (m, 5H), 0.52-0.45 (m, 2H), 0.39-0.31 (m, 1H). Synthesis of compound 31. To a solution of compound 17-3 (50 mg, 0.08 mmol) in THF (1 mL) and MeOH (1 mL) was added NaOH (63.5 mg, 1.59 mmol) and H2O (1 mL) at 25 °C. The solution was stirred at 50 °C for 16 h. The reaction solution was extracted with EtOAc (2 x 5 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum. The crude product was purified by silica gel column (PE / EtOAc = 3 / 1) to give the desired product compound 31 (4.0 mg, 12%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 2.85-2.75 (m, LCMS Rt=1 .437 min (2 min chromatography, 10-80AB), C 28 H 45 MS ESI calcd for 381 ([M-2H2O+H] + ), actual value 381. Synthesis of compound 32. To a solution of compound 17-4 (50 mg, 0.08 mmol) in THF (1 mL) and MeOH (1 mL) was added NaOH (63.5 mg, 1.59 mmol) and H2O (1 mL) at 25 °C. The reaction solution was extracted with EtOAc (5 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum. The crude product was purified by silica gel column (PE / EtOAc = 3 / 1) to give the desired product compound 32 (8.0 mg, 24%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 2.84-2.76 (m, 1H), 1.96-1.92 (m, 1H), 1.90-1.73 (m, 1H), 1.73-0.83 (m, 34H), 0.81 (s, 3H), 0.70-0.61 (m, 4H), 0.58-0.44 (m, 2H), 0.29-0.19 (m, 2H). LCMS Rt=1.436 min (2 min Chromatography, 10-80AB), C 28 H 45 MS ESI calcd for 381 ([M-2H2O+H] + ), actual value 381. Example 18. Synthesis of Compound 33 [ka] Synthesis of compound 18-2. To a solution of 2,6-di-tert-butyl-4-methylphenol (17 g, 77.1 mmol) in toluene (50 mL) was added trimethylaluminum (19.2 mL, 2 M in toluene) at 10° C. The mixture was stirred at 20° C. for 1 h. To this solution was added a solution of compound 16-3 (5 g, 12.8 mmol) in toluene (20 mL) dropwise at −70° C. under N2. The mixture was stirred at −70° C. The mixture was stirred at -70°C for 1 h. A solution of EtMgBr (12.7 mL, 3 M) was added dropwise at -70°C. The mixture was stirred at -70°C for another 3 h, and then the reaction mixture was quenched with citric acid (150 mL, saturated aqueous solution). The reaction was warmed to 25°C. The organic layer was separated and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (PE / EtOAc = 200 / 1 to 10 / 1) to give compound 18-2 (3.8 g) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 3.66 (s, 3H), 2.41-2.30 (m, 1H), 2.26-2.15 (m, 1H), 1.94 (td, J = 3.3, 12.5 Hz, 1H), 1.90-1.73 (m, 2H), 1.69-1.58 (m, 3H), 1.56-0.84 (m, 28H), 0.82 (s, 3H), 0.64 (s, 4H). Synthesis of compound 18-3. LiAlH4 (500 mg, 13.17 mmol) was added to THF (50 mL) under N2 at 0 °C. To this mixture was added a solution of compound 18-2 (1.5 g, 3.58 mmol) in THF (15 mL) at 0 °C. The mixture was stirred at 0 °C for 20 min. Water (1 mL) in THF (1 mL) was added, and an off-white solid formed from the solution. The mixture was filtered and concentrated in vacuum to give compound 18-3 (700 mg, crude) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ3.70-3.55 (brs, 2H), 1.98-1.90 (m, 1H), 1.90-1.72 (m, 1H), 1.72-0.72 (m, 39H), 0.64 (s, 3H). Synthesis of compound 18-4. To a solution of compound 18-3 (100 mg, crude) in DCM (5 mL) was added Dess-Martin reagent (215 mg) at 0 °C under N2. The mixture was stirred at 20 °C for 2 h. A solution of NaHCO3 (215 mg) and Na2S2O3 (348 mg) in water (10 mL) was added. The mixture was extracted with petroleum ether (3 × 10 mL). The organic layer was separated, washed with water (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel (PE / EtOAc = 100 / 1 to 8 / 1) to give compound 18-4 (52 mg) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 2.51-2.24 (m, 2H), 1.98-1.90 (m, 1H), 1.89-1.73 (m, 2H), 1.68-1.59 (m, 3H), 1.54-0.77 (m, 30H), 0.65 (s, 5H). Synthesis of compound 33. To a solution of compound 18-4 (52 mg, 0.134 mmol) in THF (1 mL) was added methylmagnesium bromide (0.5 mL, 1.5 mmol, 3 M in ether) at -70 °C under N2. The mixture was stirred at 20 °C for 20 min, then saturated NH4Cl (4 mL), EtOAc (5 mL) and H2O (3 mL) were added. The mixture was extracted with EtOAc (3 x 6 mL), washed with saturated NaCl (2 x 15 mL), dried over Na2SO4, filtered and concentrated in vacuum to give the crude product, which was purified by column chromatography on silica gel (PE / EtOAc = 100 / 1 to 12 / 1) to give compound 33 (18.4 mg, 30%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 3.78-3.70 (m, 1H), 1.99-1.91 (m, 1H), 1.89-1.76 (m, 1H), 1.68-0.80 (m, 41H), 0.65 (s, 4H). LCMS R t = 1.448 min (2 min chromatography, 10-80AB_E), C 27 H 45 [M-2H2O+H] + MS ESI calculated value 369, found value 369. Example 19. Synthesis of Compound 34 [ka] Synthesis of compound 34. To a solution of compound 18-4 (250 mg, crude) in THF (20 mL) was added ethylmagnesium bromide (2.2 mL, 6.6 mmol, 3 M in ether) at -70 °C under N2. The mixture was stirred at 20 °C for 1 h and then washed with saturated N H4Cl (20 mL), EtOAc (20 mL) and H2O (10 mL) were added. The mixture was extracted with EtOAc (20 mL x 3), washed with saturated NaCl (60 mL x 2), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel (PE / EtOAc = 100 / 1 to 12 / 1) to give compound 34 (80 mg) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 3.53-3.42 (m, 1H), 2.00-1.92 (m, 1H), 1.89-1.75 (m, 1H), 1.69-1.58 (m, 3H), 1.56-0.84 (m, 37H), 0.82 (s, 3H), 0.68-0.59 (m, 4H).LCMS R t = 1.526 min (2 min chromatography, 10-80AB_E), C 28 H 47 [M-2H2O+H] + MS ESI calculated value 383, measured value 383. Example 20. Synthesis of Compounds 35 and 36 [ka] Synthesis of compound 20-2. To a solution of compound 34 (64 mg, 0.153 mmol) in pyridine (3 mL), benzoyl chloride (32.2 mg, 0.229 mmol) and triethylamine (23.1 mg, 0.229 mmol) were added. The mixture was stirred at 25° C. for 5 h, and then the reaction mixture was quenched with saturated NH4Cl (6 mL). The mixture was extracted with EtOAc (3×6 mL), washed with saturated NaCl (2×15 mL), dried over Na2SO4, filtered, and concentrated in vacuum to give the crude product, which was purified by column chromatography on silica gel (PE / EtOAc=50 / 1 to 10 / 1) to give compound 20-2 (70 mg, crude). LCMS R t = 1.257 min (1.5 min chromatography, 5-95AB), C 28 H 47 [M-BzOH-H2O+H] + MS ESI calculated value 383, measured value 383. Synthesis of compounds 20-3 and 20-4. (SFC). Compound 20-2 (70 mg, crude) was purified by SFC (column: IC (250 mm * 30 mm, 10 um; Conditions: base-IPA; Gradient: 35% B; Flow rate: 80 mL / min) to give compound 20-3 (18 mg, Rt=5.988 min) and compound 20-4 (30 mg, Rt=6.229 min). Synthesis of compound 35. To a solution of compound 20-3 (18 mg, 0.03442 mmol) in THF (1 mL) and MeOH (1 mL) was added aqueous NaOH (1 mL, 20%). The mixture was stirred at 20° C. for 20 h. The mixture was concentrated in vacuum, extracted with EtOAc (2×2 mL), washed with NaHCO3 (3×4 mL) and brine (2×3 mL), dried over Na2SO4, filtered, and concentrated in vacuum to give compound 35 (8.5 mg, 59%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 3.55-3.40 (m, 1H), 2.00-1.90 (m, 1H), 1.85-1.75 (m, 1H), 1.65-1.55 (m, 4H), 1.50-0.85 (m, 36H), 0.82 (s, 3H), 0.65-0.60 (m, 4H).LCMS t R = 1.322 min (2 min chromatography, 30-90AB_E), C 28 H 47 [M-2H2O+H] + MS ESI calculated value 383, measured value 383. Synthesis of compound 36. To a solution of compound 20-4 (30 mg, 0.057 mmol) in THF (1 mL) and MeOH (1 mL) was added aqueous NaOH (1 mL, 20%). The mixture was stirred at 20° C. for 20 h. The mixture was concentrated in vacuum, extracted with EtOAc (2×2 mL), washed with NaHCO3 (3×4 mL) and brine (2×3 mL), dried over Na2SO4, filtered, and concentrated in vacuum to give compound 36 (5.2 mg). , 22%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 3.55-3.40 (m, 1H), 2.00-1.90 (m, 1H), 1.85-1.75 (m, 1H), 1.65-1.55 (m, 4H), 1.50-0.85 (m, 36H), 0.82 (s, 3H), 0.65-0.60 (m, 4H) LCMS t R = 1.507 min (2 min chromatography, 30-90AB_E), C 28 H 47 [M-2H2O+H] + MS ESI calculated value 383, measured value 383. Example 21. Synthesis of Compound 37 [ka] To a solution of compound 18-4 (50 mg, crude) in THF (20 mL) was added isopropylmagnesium bromide (3.2 mL, 6.4 mmol, 2 M in THF) at -70 °C under N2. The mixture was stirred at 20 °C for 1 h. To the mixture was added saturated NH4Cl (20 mL), EtOAc (20 mL) and H2O (10 mL). The mixture was extracted with EtOAc (3 x 20 mL), washed with saturated NaCl (2 x 60 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel (PE / EtOAc = 100 / 1 to 12 / 1) to give compound 37 (5.3 mg) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 3.35-3.27 (m., 1H), 1.96 (d, J = 12.8 Hz, 1H), 1.88-1.76 (m, 1H), 1.73-1.58 (m, 5H), 1.53-0.84 (m, 37H), 0.82 (s, 3H), 0.68-0.59 (m, 4H).LCMS t R = 1.371 min (2 min chromatography, 30- 90AB_E), C 29 H 49 [M-2H2O+H] + MS ESI calculated value 397, found value 397. Example 22. Synthesis of Compound 38 [ka] A solution of compound 18-4 (250 mg, crude) in THF (20 mL) was added to cyclopropylmagnesium bromide (12.8 mL, 6.4 mmol, 0.5 M in THF) under N2 at -70 °C. The mixture was stirred at 20 °C for 1 h. To the mixture were added saturated NH4Cl (20 mL), EtOAc (20 mL) and H2O (10 mL). The mixture was extracted with EtOAc (3 x 20 mL), washed with saturated NaCl (2 x 60 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel (PE / EtOAc = 100 / 1 to 12 / 1) to give compound 38 (110 mg, 40%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 2.85-2.75 (m, 1H), 2.00-1.92 (m, 1H), 1.89-1.76 (m, 1H), 1.69-1.59 (m, 4H), 1.55-0.85 (m, 32H), 0.82 (s, 3H), 0.65 (s, 4H), 0.56-0.43 (m, 2H), 0.29-0.16 (m, 2H).LCMS t R = 1.518 min (2 min chromatography, 10-80AB_E), C 29 H 47 [M-2H2O+H] + MS ESI calculated value 395, found value 395. Example 23. Synthesis of Compounds 39 and 40 [ka] Synthesis of compound 23-2. To a solution of compound 38 (80 mg, 0.186 mmol) in pyridine (3 mL), benzoyl chloride (39.1 mg, 0.279 mmol) and triethylamine (28.1 mg, 0.279 mmol) were added. The mixture was stirred at 25° C. for 5 h. The reaction mixture was quenched with saturated NH4Cl (6 mL). The mixture was extracted with EtOAc (3×6 mL), washed with saturated NaCl (2×15 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel (PE / EtOAc=50 / 1 to 10 / 1) to give compound 23-2 (80 mg, crude). LCMS t R = 1.247 min (1.5 min chromatography, 5-95AB_E), C 29 H 47 [M-BzOH-H2O+H] + MS ESI calculated value 395, found value 395. Synthesis of compounds 23-3 and 23-4. Compound 23-2 (80 mg, crude) was purified by SFC (column: IC (250 mm * 30 mm, 10 um; Conditions: base-IPA; Gradient: 30% B; Flow rate: 50 mL / min) to give compound 23-3 (23 mg, Rt=6.153) and compound 23-4 (35 mg, Rt=6.357). Synthesis of compound 39. To a solution of compound 23-3 (23 mg, 0.04 mmol) in THF (1 mL) and MeOH (1 mL) was added aqueous NaOH (2 mL, 20%). The mixture was stirred at 20° C. for 20 h. The mixture was concentrated in vacuo, extracted with EtOAc (2×2 mL), washed with NaHCO3 (3×4 mL) and brine (2×3 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a solid, which was purified by column chromatography on silica gel (PE / EtOAc=100 / 1 to 8 / 1) to give compound 39 (9 mg, 49%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 2.85-2.75 (m, 1H), 2.00-1.92 (m, 1H), 1.89-1.76 (m, 1H), 1.75-1.59 (m, 6H), 1.55-0.89 (m, 30H), 0.82 (s, 3H), 0.70-0.60 (m, 4H), 0.56-0.43 (m, 2H), 0.29-0.16 (m, 2H) LCMS t R =1.484 min (2 min chromatography, 30-90AB_E), C 29 H 47 [M-2H2O+H] + MS ESI calculated value 395, found value 395. Synthesis of compound 40. To a solution of compound 23-4 (35 mg, 0.065 mmol) in THF (1 mL) and MeOH (1 mL) was added aqueous NaOH (2 mL, 20%). The mixture was stirred at 20° C. for 20 h. The mixture was concentrated in vacuum, extracted with EtOAc (2×2 mL), washed with NaHCO3 (3×4 mL) and brine (2×3 mL), dried over Na2SO4, filtered, and concentrated in vacuum to give compound 40 (14 mg, 50%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 2.85-2.75 (m, 1H), 2.00-1.92 (m, 1H), 1.89-1.76 (m, 1H), 1.69-1.59 (m, 2H), 1.55-0.85 (m, 34H), 0.82 (s, 3H), 0.65 (m, 4H), 0.56-0.43 (m, 2H), 0.29-0.16 (m, 2H) LCMS t R = 1.510 min (2 min chromatography , 30-90AB_E), C 29 H 47 [M-2H2O+H] + MS ESI calculated value 395, found value 395. Example 24. Synthesis of Compound 41 [ka] Step 1. To a solution of G1a-1 (1 g, 7.4 mmol) in THF (7 mL) under N2, t- BuLi (9.25 mL, 1.6 M in pentane, 14.8 mmol) was added dropwise at −60° C. After addition, the mixture was slowly warmed to −40° C. over 0.5 h to give a solution of G1a in THF, which was used directly for the next step. Step 2. To THF (2 mL) under N2 was added G1a (0.87 mL, 0.46 M in THF and pentane, 0.402 mmol) at -70 °C. After stirring at -70 °C for 5 min, a solution of compound 10-4 (50 mg, 0.314 mmol) in THF (3 mL) was added. The reaction mixture was gradually warmed to 15 °C over 10 h. The mixture was quenched with 10 mL of saturated NH4Cl and extracted with 50 mL of EtOAc. The separated organic phase was washed with 10 mL of brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with PE / EtOAc = 10 / 1 to 2 / 1 to give compound 41 (7.3 mg, 13%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ. 5.35-5.25 (m, 1H), 3.49-3.32 (m, 1H), 2.48-2.38 (m, 1H), 2.38-2.25 (m, 1H), 2.05-1.71 (m, 12H), 1.50-0.86 (m, 29H), 0.72-0.63 (m, 3H). LCMS Rt=1.300 min (2 min chromatography, 30-90AB_E.M), C 29 H 45 [M-2H2O+H] + MS ESI calculated value 393, found value 393. Step 3. Compound 41 (800 mg, 1.86 mmol) was purified by SFC (column: AD (250 mm *30 mm, 5 um). Conditions: 0.1% NH3H2O ​​ETOH. Gradient: 40% B. Flow rate: 40 mL / min) to give compound 41-A (123 mg, 15%) as an off-white solid and compound 41-B (109 mg, 14%) as an off-white solid. Compound 41-A: 1 H NMR (400 MHz, CDCl3) δ 5.32-5.28 (m, 1H), 3.46-3.38 (m, 1H), 2.46-2.27 (m, 2H), 2.02-1.67 (m, 13H), 1.55-1.36 (m, 8H), 1.31-1.22 (m, 2H), 1.19-1.06 (m, 8H), 1.05-0.89 (m, 10H), 0.67 (s, 3H). LCMS Rt=1.321 min (2.0 min chromatography, 30-90AB), C 29 H 45 [M+H-2H2O] + MS ESI calculated value 393, found value 393. Compound 41-B: 1 H NMR (400 MHz, CDCl3) δ 5.33-5.28 (m, 1H), 3.49-3.42 (m, 1H), 2.45-2.39 (m, 1H), 2.36-2.28 (m, 1H), 2.04-1.66 (m, 12H), 1.53-1.22 (m, 10H), 1.20-0.98 (m, 12H), 0.96-0.77 (m, 7H), 0.68 (s, 3H). LCMS Rt=1.316 min (2.0 min chromatography, 30-90AB), C 29 H 45 [M+H-2H2O] + MS ESI calculated value 393, found value 393. Example 25. Synthesis of Compound 42 [ka] To THF (1 mL) under N2 was added cyclopentylmagnesium chloride (0.402 mL, 1.0 M in THF, 0.402 mmol) at -70 °C. After stirring at -70 °C for 5 min, a solution of compound 10-4 (50 mg, 0.134 mmol) in THF (4 mL) was added. The reaction mixture was gradually warmed to 15 °C over 18 h. The mixture was quenched with 10 mL of saturated NH4Cl and extracted with 50 mL of EtOAc. The separated organic phase was washed with 10 mL of brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column eluted with PE / EtOAc = 10 / 1 to 2 / 1 to give compound 42 (4.1 mg, 7%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ. 5.35-5.25 (m, 1H), 3.40-3.29 (m, 1H), 2.46-2.37 (m, 1H), 2.05-1.60 (m, 12H), 1.55-0.82 (m, 32H), 0.72-0.61 (m, 3H). LCMS Rt=1.389 min (2 min chromatography, 30-90AB_E.M), C 30 H 47 [M-2H2O+H] + MS ESI calculated value 407, measured value 407. Example 26. Synthesis of Compound 43 [ka] To THF (1 mL) under N2 was added cyclohexylmagnesium chloride (0.402 mL, 2.0 M in THF, 0.804 mmol) at -70 °C. After stirring at -70 °C for 5 min, a solution of compound 10-4 (100 mg, 0.268 mmol) in THF (1 mL) was added. The reaction mixture was gradually warmed to 15 °C over 18 h. The mixture was quenched with 10 mL of saturated NH4Cl and extracted with 50 mL of EtOAc. The separated organic phase was washed with 10 mL of brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column eluted with PE / EtOAc, 10 / 1 to 2 / 1 to give compound 43 (20 mg, 16%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ. 5.40-5.25 (m, 1H), 3.40-3.26 (m, 1H), 2.51-2.30 (m, 1H), 2.09-1.91 (m, 3H), 1.90-1.59 (m, 10H), 1.55-0.85 (m, 33H), 0.68 (s, 3H). LCMS Rt=1.490 min (2 min chromatography). -, 30-90AB_E.M), C 31 H 49 [M-2H2O+H] + MS ESI calculated value 421, measured value 421. Example 27. Synthesis of compound 44 [ka] Step 1. To a vigorously stirred suspension of Mg turnings (602 mg, 24.8 mmol) and iodine (31.3 mg, 0.124 mmol) in THF (5 mL) under N2, G5-1 (0.15 g, 1.24 mmol) was added. The mixture was heated to 60° C. After the reaction started, G5-1 (1.35 g, 11.16 mmol) in THF (6 mL) was added slowly. After the addition, the mixture was stirred at 60° C. for 2 h to give a grey suspension of G5 in THF, which was used directly for the next step. Step 2. G5 (0.402 mL, 1.0 M in THF, 0.402 mmol) was added to THF (2 mL) under N2 at -70 °C. After stirring at -70 °C for 5 min, a solution of compound 10-4 (50 mg, 0.314 mmol) in THF (3 mL) was added. The reaction mixture was gradually warmed to 15 °C and stirred for 18 h. The mixture was quenched with 10 mL of saturated NH4Cl and extracted with 50 mL of EtOAc. The separated organic phase was washed with 10 mL of brine, dried over Na2SO4, and concentrated. The residue was purified by flash column eluted with PE / EtOAc = 10 / 1 to 2 / 1 to give compound 44 (10 mg, 16%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 5.38-5.25 (m, 1H), 4.11-3.89 (m, 2H), 3.42-3.24 (m, 3H), 2.47-2.36 (m, 1H), 2.04-1.91 (m, 3H), 1.90-1.59 (m, 6H), 1.53-1.45 (m, 14H), 1.40-0.86 (m, 17H), 0.68 (s, 3H). LCMS Rt=1.187 min (2 min chromatography, 30-90AB_E.M), C 30 H 49 O2 [M-H2O+H] + MS ESI calculated value 441, measured value 441. Step 3. The product, compound 44 (830 mg, 1.80 mmol), was purified by SFC (column: AD (250 mm * 30 mm, 5 um); Conditions: 0.1% NHHO IPA; Gradient 40% B; Gradient time (min): 30; Flow rate (ml / min): 60) to give compound 44-A (142 mg, 17%) as a white solid and compound 44-B (220 mg, 27%) as a white solid. Compound 44-A: 1H NMR (400 MHz, CDCl3) δ 5.33-5.28 (m, 1H), 4.05-3.96 (m, 2H), 3.43-3.30 (m, 3H), 2.46-2.38 (m, 1H), 2.05-1.92 (m, 3H), 1.91-1.66 (m, 4H), 1.65-1.57 (m, 2H), 1.54-1.41 (m, 10H), 1.40-1.20 (m, 5H), 1.19-1.06 (m, 7H), 1.05-0.88 (m, 9H), 0.68 (s, 3H). LCMS Rt=1.167 min (2 min chromatography, 30-90AB_2MIN_E.M), C 30 H 49 O2[M+H-H2O] + MS ESI calculated value 441, measured value 441. Compound 44-B: 1 H NMR (400 MHz, CDCl3) δ 5.34-5.27 (m, 1H), 4.06-3.97 (m, 2H), 3.43-3.28 (m, 3H), 2.47-2.38 (m, 1H), 2.04-1.92 (m, 3H), 1.89-1.66 (m, 4H), 1.64-1.57 (m, 5H), 1.53-1.35 (m, 9H), 1.33-1.21 (m, 3H), 1.21-1.07 (m, 7H), 1.06-0.90 (m, 9H), 0.68 (s, 3H).LCMS Rt = 1.163 min (2 min chromatography, 30-90AB_2MIN_E.M ), C 30 H 49 O2[M+H-H2O] + MS ESI calculated value 441, measured value 441. Example 28. Synthesis of Compounds 45 and 46 [ka] Synthesis of compound 28-1. To THF (5 mL) at -70°C under N2 was added n-BuLi (2.96 mL, 2.5 M in hexane, 7.42 mmol). Then, a suspension of A-6 (1 g, 2.12 mmol) in THF (8 mL) was added dropwise to give a pale yellow suspension. After stirring at -70°C for 30 min, a solution of 2-(2,2,2-trifluoroethyl)oxirane (320 mg, 2.52 mmol) in THF (5 mL) was added. The reaction mixture was stirred at -70°C for 10 min, warmed to 15°C, and stirred for 16 h. The reaction was quenched with saturated NH4Cl (40 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give compound 28-1 (1.15 g, crude) as a pale yellow solid, which was used directly in the next step. Synthesis of Compounds 45 and 46. To a solution of compound 28-1 (1.15 g, 1.92 mmol) in 25 mL of dry MeOH, magnesium turnings (0.2 g, 8.22 mmol) (activated with 0.5% aqueous HCl, water, dry EtOH and MTBE) and NiCl2 (49.7 mg, 0.384 mmol) were added under N2 with stirring at 50 °C to induce continuous hydrogen evolution. After adding 10 batches of 0.2 g of magnesium turnings, the reaction mixture was quenched with 2 M HCl (250 mL) at 10 °C until the solids dissolved. The mixture was extracted with EtOAc (400 mL). The organic layer was washed with saturated NaHCO3 (50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column eluted with PE:EtOAc=20:1-5:1 to give 300 mg of impure product as an off-white solid. The impure product was further purified by SFC (column: Chiralpak AD-3 150×4.6 mm ID, 3 um mobile phase: A:CO2B:methanol (0.05% DEA) gradient: 5%-40% B in 5 min and hold at 40% for 2.5 min, then 5% B for 2.5 min, flow rate: 2.5 mL / min column temperature: 35° C.) to give compound 45 (99.9 mg, 11%) and compound 46 (84 mg, 10%). Compound 45: 1H NMR (400 MHz, CDCl3) δ 5.38-5.25 (m, 1H), 4.06-3.88 (m, 1H), 2.48-2.35 (m, 1H), 2.32-2.18 (m, 2H), 2.08-1.90 (m, 3H), 1.87-1.63 (m, 4H), 1.60-1.45 (m, 12H), 1.40-0.83 (m, 16H), 0.68 (s, 3H). LCMS Rt=1.203 min (2 min chromatography, 30-90AB_2MIN_E.M), C 27 H 42 F3O[M+H-H2O] + MS ESI calculated 439, found 439. SFC Rt=4.933 min (10 min chromatography, AD_3_MeOH_DEA_5_40_25ML). Compound 46: 1 H NMR (400 MHz, CDCl3) δ 5.35-5.25 (m, 1H), 4.01-3.88 (m, 1H), 2.45-2.35 (m, 1H), 2.32-2.18 (m, 2H), 2.05-1.91 (m, 3H), 1.90-1.60 (m, 4H), 1.60-1.45 (m, 12H), 1.40-0.83 (m, 16H), 0.69 (s, 3H). LCMS Rt=1.205 min (2 min chromatography, 30-90AB_2MIN_E.M), C 27 H 42 F3O[M+H-H2O] + MS ESI calculated 439, found 439. SFC Rt=5.640 min (10 min chromatography, AD_3_MeOH_DEA_5_40_25ML). Example 29. Synthesis of Compound 47 [ka] To a solution of compound 45 (140 mg, 0.307 mmol) in MeOH / THF (10 mL / 1 mL) was added Pd / C (dry, 10%, 350 mg) under Ar. After degassing with N2 three times, the reaction mixture was degassed with H2 three times. The reaction mixture was stirred at 55 °C under H2 atmosphere (50 Psi) for 16 h. The catalyst was removed by aspiration and the filtrate was concentrated to give the crude product, which was purified by silica gel column (EtOAc in PE, 10%-15%) to give compound 47 (30 mg, 21%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 3.96-3.94 (m, 1H), 2.30-2.21 (m, 2H), 1.97-1.93 (m, 1H), 1.92-1.81 (m, 2H), 1.80-1.58 (m, 4H), 1.55-1.26 (m, 6H), 1.24-1.20 (m, 11H), 1.19-0.93 (m, 11H), 0.80 (s, 3H), 0.66-0.62 (m, 4H). LCMS Rt=1.220 min (2 min chromatography, 30-9 0AB), C 27 H 44 F3O[M+H-H2O] + MS ESI calculated value 441, measured value 441. Example 30. Synthesis of compound 48 [ka] To a solution of compound 46 (102 mg, 0.223 mmol) in MeOH / THF (10 mL / 1 mL) was added Pd / C (dry, 10%, 350 mg) under Ar. After degassing with N2 three times, the reaction mixture was degassed with H2 three times. The reaction mixture was stirred under H2 atmosphere (50 Psi) at 55 °C for 16 h. The catalyst was removed by aspiration and the filtrate was concentrated to give the crude product, which was purified by silica gel column (EtOAc in PE, 10%-15%) to give compound 48 (25 mg, 24%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 4.00-3.95 (m, 1H), 2.29-2.26 (m, 2H), 1.97-1.93 (m, 1H), 1.92-1.81 (m, 2H), 1.80-1.58 (m, 4H), 1.55-1.26 (m, 6H), 1.24-1.20 (m, 11H), 1.19-0.93 (m, 11H), 0.80 (s, 3H), 0.66-0.64 (m, 4H). LCMS Rt=1.218 min (2 min chromatography, 30-9 0AB), C 27 H 44 F3O[M+H-H2O] + MS ESI calculated value 441, measured value 441. Example 31. Synthesis of Compounds 49, 50, and 51 [ka] Synthesis of K2. To 150 mL of 30% H2O2 aqueous solution, MoO3 (3 g, 208 mmol) was added. The mixture was stirred at 40°C for 5 h to form a yellow solution with suspended white solids. After cooling to 20°C, the suspension was filtered through a 1 cm mat of Celite. The yellow filtrate was cooled to 10°C (using an ice bath and magnetic stirring) and HMPA (37.2 g, 208 mmol) was added dropwise. A yellow crystalline precipitate formed. After filtration, the yellow product was recrystallized from 100 mL of EtOH at -20°C to give 52 g of crude K2 as a yellow solid. Synthesis of K3. K2 (52 g, 138 mmol) was dried over P2O5 in vacuum for 6 h to give 50 g of a yellow solid. The yellow solid was dissolved in 150 mL of THF at 20 °C. Pyridine (11.1 g, 140 mmol) was added. After stirring at 20 °C for 10 min, a yellow crystalline solid was obtained. After filtration, the filter cake was washed with THF (50 mL), MTBE (200 mL), and dried in vacuum to give 48 g of crude K3 as a yellow solid, which was used directly. Synthesis of compound 29-2. To a solution of diisopropylamine (1.81 mL, 12.9 mmol) in THF (80 mL) at -70°C under N2, a solution of n-BuLi (5.15 mL, 12.9 mmol, 2.5 M in hexane) was added dropwise. After stirring at -70°C for 10 min, the reaction mixture was gradually warmed to 10°C over 0.5 h. After cooling to -70°C, a solution of compound 29-1 (2 g, 10.8 mmol) in THF (20 mL) was added. The reaction mixture was stirred for 0.5 h. K3 (7.06 g, 16.2 mmol) was added. After stirring at -20°C for 3 h, the mixture was quenched with 200 mL of saturated Na2SO3 and extracted with MTBE (2 x 200 mL). The combined organic phase was washed with 100 mL of brine, dried over NaSO4, filtered and concentrated to give 2.1 g of crude product as a brown oil. 1 H NMR (400 MHz, CDCl3) δ. 4.55 (s, 1H), 4.37-4.24 (m, 2H), 3.16-3.03 (m, 1H), 2.78-2.66 (m, 1H), 1.32 (t, J = 6.8 Hz, 3H), 1.09 (d, J = 6.8 Hz, 3H). Synthesis of compound 29-3. To a solution of compound 29-2 (2.1 g, 10.4 mmol) in THF (100 mL) was added LiAlH4 (789 mg, 20.8 mmol) in small portions under N2 at -10°C. The reaction mixture was stirred at 15°C for 2 h. The reaction was quenched by dropwise addition of water (1 mL), 15% aqueous NaOH (1 mL) and water (3 mL) at 0°C. After stirring at 15°C for 15 min, 2 g of MgSO4 was added at 15°C. The mixture was stirred at this temperature for 1 h. After filtration through Celite in vacuum and washing with DCM (2 x 100 mL), the organic layer was concentrated in vacuum to give 2 g of crude product as a yellow oil. 1H NMR (400 MHz, CDCl3) δ. 4.09-4.03 (m, 1H), 3.69-3.61 (m, 2H), 2.39-2.27 (m, 1H), 2.21 (d, J = 4.0 Hz, 1H), 1.20 (d, J = 7.2 Hz, 3H). Synthesis of compound 29-4. To a solution of compound 29-3 (2 g, 12.6 mmol) in pyridine (15 mL) was added TsCl (2.87 g, 15.1 mmol) in portions during 5 min at 0 °C. The reaction solution was stirred at 15 °C for 16 h. The reaction mixture was quenched with 2N HCl (95 mL) at 0 °C until pH = 1-2. The internal temperature was kept below 30 °C and the mixture was extracted with MTBE (2 x 250 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by column (0-20% EtOAc in PE) to give compound 29-4 (2.1 g, 53%) as a pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ. 7.80 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 4.22-4.15 (m, 1H), 4.06-3.97 (m, 2H), 2.47 (s, 3H), 2.41-2.29 (m, 1H), 2.18 (d, J = 4.8 Hz, 1H), 1.14 (d, J = 7.2 Hz, 3H). Synthesis of compound 29-5. To THF (3.5 mL) at -70°C under N2 was added diisopropylamine (2.35 mmol, 237 mg), followed by n-BuLi (2.22 mmol, 0.89 mL, 2.5 M in hexanes). The reaction was warmed to 15°C and cooled back to -70°C. A suspension of A-6 (0.637 mmol, 300 mg) in THF (1.5 mL) was added dropwise to give a pale yellow suspension. After stirring at -70°C for 30 min, a solution of compound 29-4 (700 μmol, 218 mg) in THF (1.5 mL) was added over 5 min (slightly exothermic, keeping internal temperature <-70°C). The reaction was stirred at 15°C for 12 h. The reaction was quenched with saturated NH4Cl (30 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated to give compound 29-5 (400 mg, crude) as a pale yellow foam which was used directly in the next step. Synthesis of compound 49. To a solution of compound 29-5 (400 mg, 0.654 mmol) in MeOH (5 mL) was added Mg powder (940 mg, 39.2 mmol) at 55 °C. The mixture was stirred at 55 °C for 16 h. The mixture was quenched with HCl (30 mL, 1N) until the mixture became clear and extracted with DCM (3 × 10 mL). The combined organic phase was washed with saturated NaHCO3 (20 mL), dried over Na2SO4, filtered, concentrated and purified by CombiFlash (0-15% EtOAc in PE) to give compound 49 (80 mg, 26%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ. 5.31-5.30 (m, 1H), 3.96-3.95 (m, 1H), 2.43-2.40 (m, 1H), 2.23-2.15 (m, 1H), 2.05-1.91 (m, 3H), 1.90-1.62 (m, 4H), 1.61-1.58 (m, 3H), 1.56-1.42 (m, 7H), 1.41-1.36 (m, 1H), 1.33-1.22 (m, 2H), 1.20-1.16 (m, 5H), 1.15-1.10 (m, 4H), 1.09-1.07 (m, 1H), 1.06-1.03 (m, 4H), 1.02-0.93 (m, 4H), 0.68 (s, 3H).LCMS Rt=1. 295 min (2 min chromatography, 30-90AB_ELSD), C 28 H 44 F3O[M+H-H2O] + MS ESI calculated value 453, measured value 453. Synthesis of compounds 50 and 51. Compound 49 (55 mg, 0.116 mmol) was purified by SFC (column: AD (250 mm * 30 mm, 5 um), gradient: (A=0.05% NH3 / H2O, B=MeOH) flow rate: 120 mL / min) to give compound 50 (15 mg, 27%) and compound 51 (11 mg, 20%) as off-white solids. Compound 50: 1 H NMR (400 MHz, CDCl3) δ. 5.31-5.30 (m, 1H), 3.96-3.95 (m, 1H), 2.43-2.40 (m, 1H), 2.23-2.15 (m, 1H), 2.05-1.91 (m, 3H), 1.90-1.58 (m, 3H), 1.56-1.45 (m, 7H), 1.44-1.35 (m, 5H), 1.34-1.20 (m, 1H), 1.19-1.11 (m, 10H), 1.10-0.85 (m, 9H), 0.68 (s, 3H). LCMS Rt=1.292 min (2 min chromatography, 30-90AB_ELSD), C 28 H44 F3O[M+H-H2O] + MS ESI calculated value 453, measured value 453. SFC Rt=5.077 min (10 min chromatography, AD_3_MeOH_DEA_5_40_25ML (UV 210 nm)). Compound 51: 1 H NMR (400 MHz, CDCl3) δ. 5.31-5.30 (m, 1H), 3.96-3.95 (m, 1H), 2.43-2.40 (m, 1H), 2.23-2.15 (m, 1H), 2.05-1.91 (m, 3H), 1.90-1.58 (m, 6H), 1.56-1.36 (m, 8H), 1.35-1.22 (m, 3H), 1.20-1.11 (m, 9H), 1.10-0.97 (m, 5H), 0.96-0.90 (m, 4H), 0.68 (s, 3H).LCMS R t=1.294 min (2 min chromatography, 30-90AB_ELSD), C 28 H 44 F3O[M+H-H2O] + MS ESI calculated value 453, measured value 453. SFC Rt=5.412 min (10 min chromatography, AD_3_MeOH_DEA_5_40_25ML (UV 210 nm)). Example 32. Synthesis of Compounds 52, 53, and 54 [ka] Step 1. To a solution of diisopropylamine (781 mg, 7.72 mmol) in THF (8 mL) was added a solution of n-BuLi (2.8 mL, 2.5 M in hexane, 7.10 mmol) dropwise under N2 at -78 °C. The mixture was warmed to 0 °C. To a suspension of 32-1 (1.5 g, 3.09 mmol) in THF (15 mL) was added the freshly prepared LDA solution dropwise under N2 at -78 °C. The mixture was stirred at -78 °C for 30 min. A solution of 2-(2,2,2-trifluoroethyl)oxirane (583 mg, 4.63 mmol) in THF (6 mL) was added. The mixture was stirred at -78 °C for 30 min, warmed to 25 °C and stirred for 48 h. The reaction mixture was quenched with water (100 mL) and HCl (1 M, aq) at 15 °C until pH = 5. The mixture was extracted with EtOAc (500 mL). The separated organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column (10-50% EtOAc in PE) to give 32-2 (1.4 g, 74%) as an off-white solid, which was used directly. Step 2. To a solution of 32-2 (1.4 g, 2.29 mmol) in 20 mL of dry MeOH was added Mg powder (1.64 g, 68.7 mmol) under N2 at 60 °C. The reaction mixture was quenched with 2 M HCl (250 mL) at 10 °C until the solid dissolved. After extraction with EtOAc (400 mL), the organic layer was washed with saturated NaHCO3 (50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column eluted with PE / EtOAc = 20:1 to 5:1 to give compound 52 (510 mg, 47%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 5.30-5.28 (m, 1H), 3.98-3.96 (m, 1H), 2.35-2.25 (m, 3H), 2.05-2.00 (m, 6H), 1.96-1.60 (m, 6H), 1.57-1.04 (m, 11H), 1.03-0.92 (m, 8H), 0.86-0.83 (m, 6H), 0.68 (s, 3H). LCMS R t=1.299 min (2 min chromatography, 30-90AB), C 28 H 44 F3O[M+H-H2O] + MS ESI calculated value 453, measured value 453. Step 3. Compound 52 (510 mg, 1.08 mmol) was separated by SFC (column: AD (250 mm * 30 mm, 5 um); mobile phase: supercritical CO2 / MeOH+NH3H2O=40 / 40; flow rate: 60 ml / min; wavelength: 220 nm) to give compound 53 (208 mg, 41%) as an off-white solid and compound 54 (212 mg, 42%). was obtained as an off-white solid. Compound 53: 1 H NMR (400 MHz, CDCl3) δ 5.29-5.27 (m, 1H), 3.96-3.93 (m, 1H), 2.40-2.20 (m, 3H), 2.06-1.92 (m, 3H), 1.88-1.59 (m, 6H), 1.52-1.34 (m, 8H), 1.33-1.22 (m, 2H), 1.05-1.00 (m, 10H), 0.96-0.93 (m, 5H), 0.85 (t, J = 7.6 Hz, 3H), 0.68 (s, 3H) LCMS Rt=1.304 min (2 min chromatography, 30-90AB), C 28 H 44 F3O[M+H-H2O] + MS ESI calculated value 453, measured value 453. Compound 54: 1H NMR (400 MHz, CDCl3) δ 5.29-5.27 (m, 1H), 4.00-3.95 (m, 1H), 2.41-2.16 (m, 3H), 2.08-1.79 (m, 4H), 1.77-1.68 (m, 2H), 1.67-1.56 L CMS Rt=1.305 min (2 min chromatography, 30-90AB), C 28 H 44 F3O[M+H-H2O] + MS ESI calculated value 453, measured value 453. Example 33. Synthesis of Compound 55 [ka] To a solution of compound 54 (186 mg, 0.395 mmol) in MeOH (20 mL) was added Pd / C (dry, 10%, 350 mg) under Ar. After degassing with N2 three times, the reaction mixture was degassed with H2 three times. The reaction mixture was stirred under H2 atmosphere (50 Psi) at 55 °C for 16 h. The catalyst was removed by aspiration and the filtrate was concentrated to give the crude product, which was purified by silica gel column (EtOAc in PE, 10%-15%) to give compound 55 (26 mg, 13%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 4.00-3.94 (m, 1H), 2.33-2.22 (m, 2H), 1.97-1.93 (m, 1H), 1.92-1.81 (m, 2H), 1.80-1.58 (m, 4H), 1.55-1.26 (m, 8H), 1.24-1.20 (m, 11H), 1.19-0.93 (m, 11H), 0.82 (s, 3H), 0.67-0.61 (m, 4H). LCMS Rt=1.273 min (2 min chromatography, 30-90AB), C 28 H46 F3O[M+H-H2O] + MS ESI calculated value 455, measured value 455. Example 34. Synthesis of Compound 56 [ka] To a solution of compound 53 (183 mg, 0.389 mmol) in MeOH (20 mL) was added Pd / C (dry, 10%, 350 mg) under Ar. After degassing with N2 three times, the reaction mixture was degassed with H2 three times. The reaction mixture was stirred under H2 atmosphere (50 Psi) at 55 °C for 16 h. The catalyst was removed by aspiration and the filtrate was concentrated to give the crude product, which was purified by silica gel column (EtOAc in PE, 10%-15%) to give compound 56 (20 mg, 10%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 3.96-3.93 (m, 1H), 2.30-2.20 (m, 2H), 1.97-1.93 (m, 1H), 1.92-1.81 (m, 2H), 1.80-1.58 (m, 4H), 1.55-1.26 (m, 8H), 1.24-1.20 (m, 11H), 1.19-0.93 (m, 11H), 0.82 (s, 3H), 0.66-0.64 (m, 4H). LCMS Rt=1.268 min (2 min chromatography, 30-90A). B), C 28 H 46 F3O[M+H-H2O] + MS ESI calculated value 455, measured value 455. Example 35. Synthesis of Compounds 57 and 58 [ka] Step 1. To a suspension of Mg (1 g, 41.1 mmol) and I2 (10 mg) in THF (1 mL) was added dropwise a solution of bromocyclobutane (2.5 g, 18.5 mmol) in THF (4 mL) at 60 °C. The mixture was stirred at 60 °C for 1 h. Then a solution of cyclobutylmagnesium bromide (18.55 mmol in 15 mL of THF) was added to a solution of 9-6 (0.5 g, 1.29 mmol) in THF (10 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h and quenched with NH4Cl (10 mL, saturated aqueous solution). The mixture was extracted with EtOAc (30 mL). The organic layer was separated, concentrated in vacuo and purified by silica gel (PE / EtOAc=10 / 1 to 7 / 1) to give the crude product, which was recrystallized from MeCN (50 mL) to give 35-1 (100 mg, 18%, 50 mg delivered) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 5.33-5.21 (m, 1H), 3.50-3.38 (m, 1H), 2.42-2.24 (m, 2H), 2.09-1.61 (m, 13H), 1.55-1.21 (m, 13H), 1.20-0.89 (m, 14H), 0.85 (t, J = 7.6 Hz, 3H), 0.70-0.64 (m, 3H). LCMS Rt=1.612 min (2.0 min chromatography, 30-90AB_E, weak MS), C 30 H 49 O[M+H-H2O] + MS ESI calculated value 425.3778, found value 425.3779. Step 2. 440 mg of 35-1 was purified by SFC (instrument: SFC-14; method: column: AD (250 mm *30 mm, 5 um; Conditions: 0.1% NH3H2O ​​EtOH; Start B: 40%; End B: 40%; Gradient Time (min): 100% B Retention Time (min): Flow Rate (ml / min): 60 ML / min; Injection Volume: 160) to give Compound 57 (100 mg, 23%, 50 mg delivered) and Compound 58 (130 mg, SFC impure). The impure Compound 57 (130 mg) was separated by SFC (column: AD (250 mm * 30 mm, 5 um); Conditions: 0.1% NH3H2O ​​ETOH, 40% B; Flow rate (ml / min): 60) to give compound 58 (112 mg, 26%) as an off-white solid. Compound 57: 1 H NMR (400 MHz, CDCl3) δ 5.35-5.22 (m, 1H), 3.480-3.37 (m, 1H), 2.40-2.28 (m, 2H), 2.09-1.61 (m, 13H), 1.55-1.21 (m, 13H), 1.20-0.89 (m, 14H), 0.85 (t, J = 7.6 Hz, 3H), 0.67 (s, 3H).HP LC Rt = 5.51 min (8.0 min chromatography, 50-100_AB_E). 30 H 49 O[M+H-H2O] + MS ESI calculated value 425.3778, found value 425.3770. Compound 58: 1 H NMR (400 MHz, CDCl3) δ 5.35-5.22 (m, 1H), 3.480-3.37 (m, 1H), 2.40-2.28 (m, 2H), 2.09-1.61 (m, 13H), 1.55-1.21 (m, 14H), 1.20-0.89 (m, 13H), 0.85 (t, J = 7.6 Hz, 3H), 0.68 (s, 3H). LC MS Rt=1.361 min (2.0 min chromatography, 30-90AB_E), C30H47 [M+H-2H2O] +MS ESI calculated value 407, measured value 407. Example 36. Synthesis of compounds 36-6, 59, 59-A, 59-B, 60, 60-A and 60-B [ka] Step 1. To a solution of 16-1 (20 g, 51.4 mmol) in DCM (200 mL) was added DMP (43.2 g, 102 mmol) at 30° C. The reaction mixture was stirred at 30° C. for 1 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (100 mL). The mixture was filtered. The DCM layer was separated and the aqueous phase was extracted with DCM (100 mL). The combined organic phase was washed with saturated aqueous Na2S2O3 (150 mL), brine (150 mL), dried over Na2SO4, filtered and concentrated to give 36-1 (20 g, crude) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 5.37-5.31 (m, 1H), 3.66 (s, 3H), 3.32-3.24 (m, 1H), 2.86-2.78 (m, 1H), 2.49-2.19 (m, 5H), 2.08-2.02 (m, 3H), 1.91-1.75 (m, 2H), 1.55-1.39 (m, 5H), 1.38-1.27 (m, 5H), 1.20-1.01 (m, 5H), 0.94-0.91 (m, 3H), 0.73-0.66 (m, 4H). Step 2. To a solution of BHT (73.9 g, 336 mmol) in anhydrous toluene (100 mL) at 0° C. under N2, trimethylaluminum (2 M in toluene, 77.5 mL, 155 mmol) was added dropwise. The mixture was stirred at 15° C. for 1 h and cooled to −70° C. A solution of 36-1 (20 g, 51.7 mmol) in toluene (50 mL) was added below −60° C. The resulting mixture was stirred at −70° C. for 1 h. Ethyl magnesium bromide (51.6 mL, 3.0 M in diethyl ether, 155 mmol) was added dropwise below −60° C. The reaction mixture was stirred at −70° C. for an additional 1 h. The reaction mixture was quenched with saturated citric acid (400 mL) at −70° C. The mixture was slowly warmed to 15° C. and extracted with ethyl acetate (3×400 mL). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by Combiflash (0% to 20% EtOAc in PE) to give 36-2 (13 g, 60%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 5.31-5.25 (m, 1H), 3.66 (s, 3H), 2.47-2.16 (m, 4H), 2.07-1.69 (m, 6H), 1.66-1.59 (m, 3H), 1.55-1.38 (m, 6H), 1.36-1.23 (m, 4H), 1.20-1.00 (m, 7H), 0.98-0.81 (m, 7H), 0.67 (s, 3H). Step 3. To a solution of 36-2 (25 g, 60.0 mmol) in THF (500 mL) at 0 °C under N2, LiAlH4 (3.41 g, 90.0 mmol) was added in small portions. The reaction was stirred at 0 °C for 30 min. The reaction was quenched with 1 M HCl (300 mL) at 0 °C and extracted with EtOAc (3 x 300 mL). The combined organic phase was washed with brine (500 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by Combiflash (0% to 20% EtOAc in PE / DCM (v / v = 1 / 1)) to give 36-3 (3 g, pure) and (10 g, impure) as off-white solids. 1H NMR (400 MHz, CDCl3) δ 5.34-5.24 (m, 1H), 3.67-3.55 (m, 2H), 2.41-2.30 (m, 1H), 2.07-1.91 (m, 3H), 1.88-1.60 (m, 5H), 1.55-1.33 (m, 10H), 1.30-1.20 (m, 3H), 1.17-1.01 (m, 8H), 1.00-0.89 (m, 5H), 0.85 (t, J = 7.4 Hz, 3H), 0.68 (s, 3H). Step 4. To a solution of 36-3 (3 g, 7.71 mmol) in DCM (100 mL) was added DMP (6.52 g, 15.4 mmol) at 20° C. The reaction mixture was stirred at 20° C. for 10 min. The reaction mixture was quenched with saturated aqueous NaHCO3 (100 mL) at 20° C. The mixture was filtered. The DCM layer was separated and the aqueous phase was extracted with DCM (50 mL). The combined organic phase was washed with saturated aqueous Na2S2O3 (150 mL), brine (150 mL), dried over Na2SO4, filtered and concentrated to give 36-4 (3 g, crude) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 9.80-9.73 (m, 1H), 5.32-5.24 (m, 1H), 2.51-2.29 (m, 3H), 2.07-1.93 (m, 3H), 1.88-1.70 (m, 3H), 1.65-1.57 (m, 4H), 1.50-1.24 (m, 10H), 1.21-1.04 (m, 5H), 1.02-0.96 (m, 1H), 0.98-0.82 (m, 8H), 0.68 (s, 3H). Step 5. To a vigorously stirred suspension of Mg (1.76 g, 72.8 mmol) turnings and iodine (46.1 mg, 0.182 mmol) in THF (2 mL) under N2, 1,2-dibromoethane (68.3 mg, 0.364 mmol) and 10% of a solution of 4-chlorotetrahydro-2H-pyran (4.4 g, 36.4 mmol) in THF (18 mL) were added. The mixture was heated to 60° C., and when the reaction mixture became clear and a Grignard was formed, the remainder of the solution of 4-chlorotetrahydro-2H-pyran in THF was added slowly over 30 min. The reaction mixture was stirred at 65° C. for 2 h to give a solution of (tetrahydro-2H-pyran-4-yl)magnesium chloride in THF (approximately 2 M). The Grignard solution was used without any further purification. Under N2, a solution of 36-4 (800 mg, 2.06 mmol) in THF (150 mL) was added in one portion to the Grignard reagent at 15 °C. After stirring for 2 min at 15 °C, the mixture was quenched with 200 mL of saturated NH4Cl and 200 mL of EtOAc. The separated organic phase was washed with 200 mL of brine, dried over Na2SO4, filtered and concentrated. The residue was purified by CombiFlash (0% to 30% EtOAc in PE / DCM (v / v=1 / 1)) to give 36-5 (550 mg, 56%) as an off-white solid, providing 50 mg of 36-5. 1 H NMR (400 MHz, CDCl3) δ 5.32-5.25 (m, 1H), 4.06-3.96 (m, 2H), 3.42-3.29 (m, 3H), 2.39-2.33 (m, 1H), 2.07-1.79 (m, 6H), 1.77-1.60 (m, 7H), 1.51-1.38 (m, 10H), 1.35-1.21 (m, 4H), 1.16-1.01 (m, 8H), 0.97-0.90 (m, 4H), 0.85 (t, J = 7.4 Hz, 3H), 0.71-0.66 (m, 3H). LCMS Rt=1.212 min (2 min Chromatography, 30-90AB_2MIN_E.M), C 31 H 51 O2[M+H-H2O] + MS ESI calculated value 455, measured value 455. Step 5. 36-5 (500 mg, 1.05 mmol) was mixed with SFC (column: AD (250 mm * 30 mm, 5 um); Conditions: 0.1% NHHO IPA; Gradient 40% B; Gradient time (min): 30; Flow rate (ml / min): 60) to give compound 59 (210 mg, 42%, 50 mg delivered) as an off-white solid and compound 60 (200 mg, 40%, 45 mg delivered) as an off-white solid. Compound 59 (Peak 1): 1 H NMR (400 MHz, CDCl3) δ 5.32-5.25 (m, 1H), 4.06-3.96 (m, 2H), 3.43-3.29 (m, 3H), 2.40-2.32 (m, 1H), 2.07-1.79 (m, 4H), 1.77-1.60 (m, 4H), 1.55-1.35 (m, 14H), 1.34-1.17 (m, 5H), 1.15-0.90 (m, 12H), 0.85 (t, J = 7.4 Hz, 3H), 0.68 (s, 3H). LCMS Rt = 1.221 min (2 min chromatography, 30-90AB_2MIN_E.M), C 31 H 51 O2[M+H-H2O] + MS ESI calculated value 455, measured value 455. Compound 60 (peak 2): 1H NMR (400 MHz, CDCl3) δ 5.31-5.26 (m, 1H), 4.06-3.96 (m, 2H), 3.43-3.29 (m, 3H), 2.40-2.33 (m, 1H), 2.07-1.93 (m, 4H), 1.88-1.61 (m, 9H), 1.54-1.38 (m, 9H), 1.34-1.06 (m, 8H), 1.05-0.90 (m, 9H), 0.85 (t, J = 7.4 Hz, 3H), 0.68 (s, 3H). Rt=1.218 min (2 min chromatography, 30-90AB_2MIN_E.M), C 31 H 51 O2[M+H-H2O] + MS ESI calculated value 455, measured value 455. Step 6. To a solution of compound 59 (150 mg, 0.317 mmol) in MeOH (5 mL) and THF (5 mL) was added dry Pd / C (300 mg) at 15° C. The mixture was degassed and purged with H2 several times, then stirred under 50 psi of H2 at 55° C. for 72 h. The reaction mixture was filtered through a pad of Celite and washed with THF (2×5 mL). The filtrate was concentrated. The residue was purified by Combiflash (0-30% EtOAc in PE / DCM (v / v=1 / 1)) to give compound 59-A (20 mg, 13%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 4.06-3.94 (m, 2H), 3.43-3.27 (m, 3H), 2.00-1.67 (m, 6H), 1.55-1.48 (m, 4H), 1.45-1.32 (m, 13H), 1.29-1.12 (m, 11H), 1.07-0.89 (m, 12H), 0.65 (s, 3H). LCMS Rt=1.261 min (2.0 min chromatography, 30-90AB ), C 31 H 51 O[M+H-2H2O] + MS ESI calculated value 439, measured value 439. Step 7. To a solution of compound 59 (50 mg, 0.105 mmol) in MeOH (5 mL) and THF (5 mL) was added dry Pd(OH)2 (300 mg) at 15 °C. The mixture was degassed and purged with H2 several times and stirred under 50 psi of H2 at 55 °C for 72 h. The reaction mixture was filtered through a pad of Celite and washed with THF (2 x 5 mL). The filtrate was concentrated. The residue was purified by Combiflash (0% to 30% EtOAc in PE / DCM (v / v = 1 / 1)) to give compound 59-B (10 mg, 20%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 4.05-3.95 (m, 2H), 3.42-3.29 (m, 3H), 1.99-1.91 (m, 1H), 1.89-1.58 (m, 6H), 1.56-1.35 (m, 14H), 1.33-1.16 (m, 8H), 1.14-0.95 (m, 6H), 0.94-0.80 (m, 10H), 0.69-0.58 (m, 4H).LCMS Rt=1.253 min (2.0 min chromatograph Raffi, 30-90AB), C 31 H 51 O[M+H-2H2O] + MS ESI calculated value 439, measured value 439. Step 8. To a solution of compound 60 (150 mg, 0.317 mmol) in MeOH (5 mL) and THF (5 mL) was added dry Pd / C (300 mg) at 15° C. The mixture was degassed and purged with H2 several times and stirred under 50 psi of H2 at 55° C. for 72 h. The reaction mixture was filtered through a pad of Celite and washed with THF (2×5 mL). The filtrate was concentrated. The residue was purified by Combiflash (0%-30% EtOAc in PE / DCM (v / v=1 / 1)) to give compound 60-A (33 mg) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 4.06-3.95 (m, 2H), 3.43-3.26 (m, 3H), 2.00-1.59 (m, 9H), 1.53-1.35 (m, 11H), 1.34-1.10 (m, 13H), 1.08-0.84 (m, 13H), 0.65 (s, 3H).LCMS Rt=1.261min(2 0 min chromatography, 30-90AB), C 31 H 51 O[M+H-2H2O] + MS ESI calculated value 439, measured value 439. Step 9. To a solution of compound 60 (150 mg, 0.317 mmol) in MeOH (5 mL) and THF (5 mL) was added dry Pd / C (300 mg) at 15° C. The mixture was degassed and purged with H2 several times and stirred under 50 psi of H2 at 55° C. for 72 h. The reaction mixture was filtered to remove Pd / C and the filtrate was concentrated. The residue was purified by Combiflash (0% to 30% EtOAc in PE / DCM (v / v=1 / 1)) to give compound 60-B (40 mg, 26%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 4.06-3.95 (m, 2H), 3.43-3.27 (m, 3H), 2.03-1.91 (m, 1H), 1.86-1.74 (m, 1H), 1.72-1.57 (m, 8H), 1.54-1.34 (m, 10H), 1.33-1.15 (m, 8H), 1.15-0.96 (m, 7H), 0.94-0.79 (m, 10H), 0.72-0.56 (m, 4H). LCMS Rt=1.250 min (2.0 min chromatography, 30-90AB), C 31 H 51 O[M+H-2H2O] + MS ESI calculated value 439, measured value 439. Step 10. To a solution of 36-5 (150 mg, 0.317 mmol) in MeOH (5 mL) and THF (5 mL) was added dry Pd / C (300 mg) at 15 °C. The mixture was degassed and purged with H2 several times and stirred under 50 psi of H2 at 55 °C for 72 h. The reaction mixture was filtered through a pad of Celite and washed with THF (2 x 5 mL). The filtrate was concentrated. The residue was purified by Combiflash (0% to 30% EtOAc in PE / DCM (v / v = 1 / 1)) to give 36-6 (30 mg) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 4.07-3.94 (m, 2H), 3.43-3.25 (m, 3H), 2.00-1.59 (m, 7H), 1.50-1.36 (m, 11H), 1.34-1.10 (m, 15H), 1.07-0.82 (m, 13H), 0.65 (s, 3H).LCMS Rt=1.261min (2.0min Chromatography between 30-90AB), C 31 H 51 O[M+H-2H2O] + MS ESI calculated value 439, measured value 439. Alternative Synthesis of Examples 37.10, 11, 13 and 15 [ka] Step 2. To a mixture of DMP (539 g, 1271 mmol) in DCM (800 mL) was added 37-1 (200 g, 636 mmol) in DCM (2.2 L) at 30° C. The reaction mixture was stirred at 40° C. for 1 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (1.2 L) at 10° C. The mixture was filtered. The DCM phase in the filtrate was separated and washed with saturated aqueous NaHCO3 / Na2S2O3 (1:1, 2×1 L), brine (1 L), dried over Na2SO4, filtered and concentrated in vacuo to give a yellow solid, which was triturated in MeCN (700 mL) to give 37-2 (115 g, 58%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 5.38-5.31 (m, 1H), 4.86 (s, 1H), 4.72 (s, 1H), 3.28 (dd, J = 2.8, 16.8 Hz, 1H), 2.82 (dd, J = 1.6, 16.8 Hz, 1H), 2.56-2.40 (m, 1H), 2.35-2.24 (m, 1H), 2.11-1.99 (m, 3H), 1.95-1.85 (m, 1H), 1.85-1.77 (m, 1H), 1.76 (s, 3H), 1.73-1.61 (m, 3H), 1.56-1.39 (m, 3H), 1.31-1.19 (m, 2H), 1.19 (s, 3H), 1.18-0.99 (m, 3H), 0.61 (s, 3H). Step 3. To a mixture of BHT (405 g, 1839 mmol) in toluene (400 mL) was added AlMe3 (459 mL, 2 M, 919 mmol) dropwise at 0° C. The resulting mixture was stirred at 15° C. for 1 h. 37-2 (115 g, 368 mmol) in toluene (500 mL) was added dropwise at −70° C. The mixture was stirred at −70° C. for 1 h. EtMgBr (368 mL, 3 M, 1104 mmol) was added dropwise at −70° C. The reaction mixture was stirred at −70° C. for 1 h. The reaction mixture was poured into a saturated aqueous solution of citric acid (2 L). The aqueous phase was extracted with ethyl acetate (2×1.5 L). The combined organic phase was washed with brine (2 L), dried over Na2SO4, filtered, and concentrated in vacuo to give an off-white solid, which was purified by recrystallization in MeCN (900 mL) to give 37-3 (80 g, 63%) as an off-white solid. The filtrate was concentrated in vacuo to give a solid, which was purified by silica gel chromatography (PE:EtOAc=20:1) to give an off-white solid, which was further purified by recrystallization in MeCN (150 mL) to give 37-3 (17 g, 14%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 5.34-5.24 (m, 1H), 4.85 (s, 1H), 4.71 (s, 1H), 2.40 -2.33 (m, 1H), 2.07-1.94 (m, 3H), 1.91-1.82 (m, 3H), 1.82-1.73 (m, 4H), 1.73-1.52 (m, 8H), 1.50-1.32 (m, 4H), 1.29-1.05 (m, 5H), 1.05-0.90 (m, 1H), 0.85 (t, J = 7.6 Hz, 3H), 0.58 (s, 3H). Step 4. To a mixture of 37-3 (97 g, 283 mmol) and 9-BBN dimer (79 g, 324 mmol) was added THF (650 mL) under N2 at 15 °C. The reaction mixture was stirred at 30 °C for 1 h. The mixture was cooled to 15 °C. Ethanol (129 g, 2.83 mmol) was added at 15 °C. Aqueous NaOH (478 mL, 5 M, 2390 mmol) was added dropwise at 15 °C. H2O2 (320 g, 30%, 2.83 mmol) was added dropwise at 15 °C. The resulting mixture was stirred at 60 °C for 1 h. The reaction mixture was cooled to 20 °C. An off-white solid was formed. The solid was filtered and washed with water (2 x 800 mL). The combined solids were purified by trituration in MeCN (200 mL) to afford 15-3a-1 (91 g, impure) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 5.32-5.23 (m, 1H), 3.67-3.60 (m, 1H), 3.42-3.33 (m, 1H), 2.40-2.33 (m, 1H), 2.08-1.90 (m, 3H), 1.89-1.69 (m, 2H), 1.66-1.60 (m, 3H), 1.56-1.24 (m, 9H), 1.23-1.07 (m, 5H), 1.05 (d, J = 6.8 Hz, 3H), 1.03 (s, 3H), 1.02-0.90 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H), 0.70 (s, 3H). Step 5. To a solution of 37-4 (91 g, 252 mmol) in chloroform (500 mL) and pyridine (350 mL) was added TsCl (132.2 g, 694 mmol) at 15° C. The mixture was stirred at 15° C. for 2 h. The combined reaction mixture was concentrated in vacuo to remove most of the chloroform. To the resulting pyridine mixture was added water (3 L). An off-white solid formed which was filtered to give an off-white solid which was washed with water (6×4 L). The off-white solid was dissolved in DCM (3.5 L), dried over Na2SO4, filtered and concentrated in vacuo to give 37-5 (127 g, 98%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 5.30-5.20 (m, 1H), 4.00-3.90 (m, 1H), 3.80-3.70 (m, 1H), 2.45 (s, 3H), 2.40-2.30 (m, 1H), 2.10-1.90 (m, 3H), 1.75-1.60 (m, 6H), 1.55-1.30 (m, 5H), 1.25-0.95 (m, 13H), 0.90-0.80 (m, 5H), 0.64 (s, 3H). Step 6. To a solution of 37-5 (127 g, 246 mmol) in DMF (1 L) was added KI (196 g, 1.18 mol) at 15 °C. The mixture was stirred at 50 °C for 1 h. To the resulting mixture was added PhSO2Na (148 g, 737 mmol). The mixture was stirred at 50 °C for 16 h. The reaction mixture was poured into water (4 L) and some yellow solid formed. The mixture was filtered. The filter cake was washed with water (3 × 2 L). The resulting filter cake was dissolved in DCM (3 L), washed with water (3 × 1 L), brine (2 × 2 L), dried over Na2SO4, filtered, and concentrated in vacuum to give the crude product as a yellow solid, which was recrystallized in MeCN (400 mL) to give 32-1 (45 g, 34%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.95-7.88 (m, 2H), 7.68-7.62 (m, 1H), 7.61-7.53 (m, 2H), 5.30-5.22 (m, 1H), 3.20-3.08 (m, 1H), 2.91-2.79 (m, 1H), 2.40-2.30 (m, 1H), 2.09-1.87 (m, 4H), 1.74-1.60 (m, 4H), 1.50-1.36 (m, 7H), 1.24-0.98 (m, 13H), 0.90-0.80 (m, 4H), 0.65 (s, 3H). Step 7. To a solution of diisopropylamine (7.28 g, 72.1 mmol) in THF (20 mL) at -70°C under N2, n-BuLi (27.1 mL, 2.5 M, 67.9 mmol) was added. The resulting mixture was stirred at 0°C for 30 min. The mixture was cooled to -70°C again. To the mixture was added 32-1 (10 g, 20.6 mmol) in THF (50 mL) at -70°C. The reaction mixture was stirred at -70°C for 1 h. 2-Isopropyloxirane (2.12 g, 24.7 mmol) in THF (10 mL) was added at -70°C. The reaction mixture was slowly warmed to 15°C and stirred at 15°C for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl (100 mL) at 0°C. This The mixture was extracted with EtOAc (2×200 mL). The combined organic phase was washed with brine (150 mL), dried over Na2SO4, filtered and concentrated in vacuo to give 37-6 (12 g, crude) as a yellow solid. LCMS Rt=3.784 and 3.859 min (7 min chromatography, 30-90AB_7MIN_E.M), C 35 H 53 O3S[M+H-H2O] + MS ESI calculated value 553, measured value 553. Step 8. To a solution of 37-6 (12 g, 21.0 mmol) in 200 mL of anhydrous MeOH, Mg powder (30.6 g, 1260 mmol) and NiCl2 (27.0 mg, 0.21 mmol) were added under N2 at 50 °C with stirring to induce continuous hydrogen evolution. The reaction mixture was quenched with 2 M HCl (100 mL) until the solids dissolved. The mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with saturated NaHCO3 (50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography eluted with PE / EtOAc=20 / 1-8 / 1 to give 5.6g of an off-white solid, which was purified by SFC (column: Chiralpak AD 250×30 mm ID, 5 um mobile phase: A:CO2 B:methanol (0.1% NH3H2O) gradient: 35% to 35% B, flow rate: 60 mL / min) to give compound 10 (2.2 g, 24%), compound 11 (2.2 g, 24%) as an off-white solid. Compound 10: 1 H NMR (400 MHz, CDCl3) δ 5.32-5.23 (m, 1H), 3.38-3.24 (m, 1H), 2.41-2.32 (m, 1H), 2.10-1.92 (m, 3H), 1.91-1.78 (m, 1H), 1.76-1.58 (m, 6H), 1.53-1.22 (m, 11H), 1.19-0.98 (m, 9H), 0.98-0.80 (m, 14H), 0.68 (s, 3H). LCMS Rt=1.346 min (2 min chromatography, 30-90AB_2MIN_E.M), C 29 H 47 [M+H-2H2O] + MS ESI calculated value 395, found value 395. Compound 11: 1H NMR (400 MHz, CDCl3) δ 5.32-5.23 (m, 1H), 3.38-3.24 (m, 1H), 2.41-2.32 (m, 1H), 2.10-1.92 (m, 3H), 1.91-1.78 (m, 1H), 1.76-1.55 (m, 6H), 1.50-1.22 (m, 11H), 1.19-0.98 (m, 9H), 0.98-0.80 (m, 14H), 0.68 (s, 3H). LCMS Rt=1.344 min (2 min chromatography, 30-90AB_2MIN_E.M), C 29 H 47 [M+H-2H2O] + MS ESI calculated value 395, found value 395. Step 8A. To a solution of compound 10 (1.6 g, 3.71 mmol) in MeOH / THF (130 mL / 20 mL) was added Pd / C (dry, 10%, 5 g) under Ar. After degassing with N2 three times, the reaction mixture was degassed with H2 three times. The reaction mixture was stirred at 55 °C in H2 atmosphere (50 Psi) for 16 h. The catalyst was removed by aspiration and the filtrate was concentrated to give the crude product, which was purified by silica gel column (EtOAc in PE, 5% to 10%) to give compound 13 (815 mg, 50%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 3.31-3.30 (m, 1H), 2.00-1.92 (m, 1H), 1.89-1.78 (m, 1H), 1.58 (m, 5H), 1.57-1.48 (m, 3H), 1.47-1.30 (m, 8H), 1.30-1.16 (m, 7H), 1.15-0.94 (m, 6H), 0.93-0.85 (m, 13H), 0.82 (s, 3H), 0.70-0.60 (m, 4H). LCMS Rt=1.392 min (2 min chromatography, 30-90AB_2MIN_E.M), C 29 H 49 [M+H-2H2O] + MS ESI calculated value 397, actual value 397. Step 8B. A mixture of compound 11 (1.6 g, 3.71 mmol) and Pd / C (5 g, 10%, dry) in ethyl acetate (250 mL) was stirred under H2 (50 psi) at 50°C for 16 h. The reaction mixture was filtered. The filter cake was washed with THF (4 x 20 mL). The combined filtrate was concentrated in vacuo to give a solid, which was purified by silica gel chromatography (PE: EtOAc = 20: 1) to give compound 15 (974 mg, 61%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 3.31-3.30 (m, 1H), 2.00-1.92 (m, 1H), 1.89-1.78 (m, 1H), 1.69-1.58 (m, 5H), 1.57-1.48 (m, 3H), 1.47-1.30 (m, 8H), 1.30-1.16 (m, 7H), 1.15-0.94 (m, 6H), 0.93-0.85 (m, 13H), 0.82 (s, 3H), 0.70-0.60 (m, 4H). LCMS Rt=1.389 min (2 min chromatography, 30-90AB_2MIN_E.M), C 29 H 49 [M+H-2H2O] + MS ESI calculated value 397, found value 397. Example 38. Synthesis of Compounds 66, 67, 68, and 69 [ka] Step 1. To a solution of compound 38-1 (1.0 g, 2.60 mmol) in MeOH (15 mL) was added NaBH4 (0.21 g, 5.7 mmol) in small portions at 0 °C. The reaction mixture was then warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with saturated aqueous NH4Cl (5 mL) and extracted with CHCl2 (3 x 20 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (PE / EtOAc = 15 / 1 to 10 / 1) to give the desired product (0.82 g, 82%) as an off-white powder.1 H NMR (400 MHz, CDCl3) δ 5.35-5.29 (m, 1H), 3.76-3.73 (m, 1H), 2.45-2.40 (m, 1H), 2.01-1.95 (m, 3H), 1.94-1.68 (m, 4H), 1.67-1.53 (m, 4H), 1.51.63-1.19 (m, 18H), 1.18 (s, 3H), 1.02 (s, 3H), 0.95 (d, J=6.4 Hz, 3H), 0.68 (s, 3H). Step 2. A solution of 38-1 (0.6 g, 15.4 mmol) in MeOH (20 mL) was purified by prep-SFC to give compound 66 (180 mg, 30%) and compound 67 (240 mg, 40%). The absolute configurations of compound 66 and compound 67 were confirmed by Mosher method. 1 H NMR (Compound 66): (400 MHz, CDCl3) δ 5.35-5.28 (m, 1H), 3.80-3.70 (m, 1H), 2.48-2.38 (m, 1H), 2.07-1.65 (m, 10H), 1.65-1.20 (m, 13H), 1.20-0.95 (m, 12H), 0.95 (d, J = 6.8 Hz, 3H), 0.63 (s, 3H). 1 H NMR (Compound 67): (400 MHz, CDCl3) δ 5.34-5.28 (m, 1H), 3.80-3.70 (m, 1H), 2.47-2.40 (m, 1H), 2.04-1.93 (m, 2H), 1.93-1.68 (m, 2H), 1.68-1.21 (m, 15H), 1.20-0.96 (m, 16H), 0.95 (d, J = 6.8 Hz, 3H), 0.68 (s, 3H). Step 3A. To a solution of compound 66 (140 mg, 0.36 mmol) in EtOAc (5 mL) was added 5% Pd / C (56 mg) under N2. The suspension was degassed in vacuum and purged with H2 several times. The mixture was then stirred under H2 (50 psi) at 50°C for 12 h. The mixture was filtered through a Celite pad and the pad was washed with EtOAc (2 x 5 mL). The combined filtrate was concentrated to dryness to give the crude product, which was purified by column chromatography on silica gel (PE / EtOAc / EtOAc = 12 / 1 to 10 / 1) to give compound 68 (80 mg, 57%) and compound 69 (18 mg, 13%) as off-white powder. 1 H NMR (Compound 68)(400 MHz, CDCl3) δ 3.80-3.70 (m, 1H), 1.98-1.93 (m, 1H), 1.88-1.78 (m, 1H), 1.67-1.27 (m, 16H), 1.24-0.94 (m, 14H), 0.92 (d, J=6.4 Hz, 3H), 0.80 (s, 3H), 1.07 (s, 3H), 0.62 (m, 4H) . 1 H NMR (Compound 69)(400 MHz, CDCl3) δ 3.80-3.70 (m, 1H), 1.98-1.95 (m, 1H), 1.95-1.79 (m, 3H), 1.64-1.23 (m, 18H), 1.23-1.00 (m, 14H), 0.96 (s, 3H) 0.92 (d, J=6.0 Hz, 3H), 0.62 (s, 3H). Step 3B. To a solution of compound 67 (120 mg, 0.30 mmol) in EtOAc (5 mL) was added 5% Pd / C (48 mg) under N2. The suspension was degassed in vacuum and purged with H2 several times. The mixture was then stirred under H2 (50 psi) at 50°C for 12 h. The mixture was filtered through a Celite pad and the pad was washed with EtOAc (2 x 5 mL). The combined filtrate was concentrated to dryness to give the crude product, which was purified by column chromatography on silica gel (PE / EtOAc / EtOAc = 12 / 1 to 10 / 1) to give compound 70 (78 mg, 65%) and compound 71 (26 mg, 21%) as off-white powder. Compound 70: 1 H NMR: (400 MHz, CDCl3) δ 3.80-3.70 (m, 1H), 1.98-1.93 (m, 1H), 1.88-1.78 (m, 1H), 1.67-1.35 (m, 18H), 1.24-0.85 (m, 19H), 0.80 (s, 3H), 0.67-0.61(m, 4H). Compound 71: 1 H NMR: (400 MHz, CDCl3) δ 3.80-3.70 (m, 1H), 2.00-1.93 (m, 1H), 1.93-1.77 (m, 3H), 1.67-1.25 (m, 19H), 1.25-0.80 (m, 18H), 0.64 (s, 3H). Example 39. Synthesis of Compounds 72, 73, 74-A, 74-B, 75-A, and 75-B [ka] Step 1. nBuLi (2.06 mL, 2.5 M in hexanes, 5.15 mmol) was added dropwise to THF (3 mL) at -70°C under N2, followed by a suspension of 32-1 (1 g, 2.06 mmol) in THF (5 mL). After stirring at -70°C for 30 min, a solution of 2-(tert-butyl)oxirane (309 mg, 3.09 mmol) in THF (2 mL) was added dropwise. The mixture was stirred at -70°C for 30 min, warmed to 20°C, and stirred at 20°C for 16 h. The reaction mixture was quenched by the addition of 30 mL of saturated NH4Cl at 20°C. The organic layer was separated. The aqueous phase was extracted with EtOAc (2 x 30 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by Combiflash (0-15% EtOAc in PE) to give impure 39-1 (700 mg, impure) as an off-white solid. Step 2. A solution of 39-1 (700 mg, 1.19 mmol) in MeOH (30 mL) was heated at 55° C. Mg powder (1.15 g, 47.5 mml) was added in one portion. The mixture was stirred at 55° C. for 2 h. The mixture was quenched with HCl (2N, 100 mL) until the reaction was clear and extracted with DCM (3×50 mL). The combined organic phase was washed with water and concentrated to dryness. NaHCO3 (100 mL), dried over Na2SO4, filtered, concentrated and purified by Combiflash (0-15% EtOAc in PE) to give 39-2 (400 mg, 76%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 5.30-5.29 (m, 1H), 3.18-3.12 (m, 1H), 2.40-2.30 (m, 1H), 2.08-1.80 (m, 4H), 1.76-1.69 (m, 1H), 1.68-1.58 (m, 2H), 1.56-1.33 (m, 10H), 1.32-1.22 (m, 5H), 1.21-1.05 (m, 4H), 1.02 (s, 3H), 1.01-0.96 (m, 5H), 0.95-0.83 (m, 9H), 0.82-0.78 (m, 3H), 0.69 (s, 3H).LCMS t R=1.3 75 min (2 min chromatography, 30-90AB_ELSD), C 30 H 49 [M+H-2H2O] + MS ESI calculated value 409, measured value 409. Step 3. 350 mg of 39-2 was mixed with SFC (column: AD (250 mm * Separation from a column of 300 mL of hexanes (30 mm, 5 um), gradient: 30-30% B (A=0.05% NH3 / HO, B=MeOH), flow rate: 60 mL / min) afforded compound 72 (160 mg, 46%) and compound 73 (120 mg, 34%) as off-white solids. Compound 72: 1 H NMR (400 MHz, CDCl3) δ 5.30-5.29 (m, 1H), 3.18-3.12 (m, 1H), 2.40-2.30 (m, 1H), 2.08-1.80 (m, 4H), 1.76-1.69 (m, 1H), 1.68-1.58 (m, 2H), 1.56-1.33 (m, 10H), 1.32-1.22 (m, 5H), 1.21-1.05 (m, 4H), 1.02 (s, 3H), 1.01-0.96 (m, 5H), 0.95-0.83 (m, 9H), 0.82-0.78 (m, 3H), 0.69 (s, 3H). LCMS R = 1.389 min (2 min chromatography, 30-90AB_ELSD), C 30 H 49 [M+H-2H2O] + MS ESI calculated value 409, measured value 409. Compound 73: 1H NMR (400 MHz, CDCl3) δ 5.30-5.29 (m, 1H), 3.18-3.12 (m, 1H), 2.40-2.30 (m, 1H), 2.08-1.80 (m, 4H), 1.76-1.69 (m, 1H), 1.68-1.58 (m, 2H), 1.56-1.33 (m, 10H), 1.32-1.22 (m, 5H), 1.21-1.05 (m, 4H), 1.02 (s, 3H), 1.01-0.96 (m, 5H), 0.95-0.83 (m, 9H), 0.82-0.78 (m, 3H), 0.69 (s, 3H). LCMS R = 1.424 min (2 min chromatography, 30-90AB_ELSD), C 30 H 49 [M+H-2H2O] + MS ESI calculated value 409, measured value 409. Step 4. Synthesis of compounds 74-A and 74-B. To a solution of compound 72 (110 mg, 0.247 mmol) in MeOH (30 mL) was added Pd / C (dry, 200 mg). The mixture was stirred under H2 (50 psi) at 50°C for 72 h. The mixture was filtered, concentrated, and purified by CombiFlash (0-15% EtOAc in PE) to give compound 74-A (19 mg, 17%) as an off-white solid and compound 74-B (18 mg, 16%) as an off-white solid. Compound 74-A: 1 H NMR (400 MHz, CDCl3) δ 3.01-3.06 (m, 1H), 2.01-1.94 (m, 1H), 1.93-1.70 (m, 5H), 1.39-1.58 (m, 4H), 1.50-1.21 (m, 13H), 1.20-1.11 (m, 5H), 1.10-0.97 (m, 5H), 0.96 (s, 3H), 0.95-0.91 (m, 5H), 0.89 (s, 9H), 0.65 (s, 3H). LCMS R = 1.425 min (2 min chromatography, 30-90AB_ELSD), purity 99.4%, C 30H 51 [M+H-2H2O] + MS ESI calculated value 411, measured value 411. Compound 74-B: 1 H NMR (400 MHz, CDCl3) δ 3.11-3.07 (m, 1H), 1.98-1.94 (m, 1H), 1.88-1.58 (m, 6H), 1.56-1.40 (m, 5H), 1.39-1.15 (m, 10H), 1.13-1.02 (m, 5H), 1.01-0.96 (m, 3H), 0.95-0.92 (m, 4H), 0.91-0.83 (m, 12H), 0.81 (s, 3H), 0.70-0.50 (m, 4H). LCMS t R = 1.424 min (2 min chromatography, 30-90AB_ELSD), C 30 H 51 [M+H-2H2O] + MS ESI calculated value 411, measured value 411. Step 5. Synthesis of compounds 75-A and 75-B. To a solution of compound 73 (70 mg, 0.157 mmol) in MeOH (30 mL) was added Pd / C (dry, 150 mg). The mixture was stirred at 50 °C under H2 (50 psi) for 72 h. The mixture was filtered, concentrated, and purified by CombiFlash (0-15% EtOAc in PE) to give compounds 75-A and 75-B. Compound 75-A (10 mg, 14%) was obtained as an off-white solid, and compound 75-B (12 mg, 17%) was obtained as an off-white solid. Compound 75-A: 1 H NMR (400 MHz, CDCl3) δ 3.20-3.10 (m, 1H), 2.00-1.94 (m, 1H), 1.94-1.70 (m, 4H), 1.70-1.10 (m, 19H), 1.20-1.00 (m, 9H), 1.00-0.80 (m, 17H), 0.65 (s, 3H).LCMS t R = 1.424 min (2 min chromatography, 30-90AB_ELSD), C 30 H 51[M+H-2H2O] + MS ESI calculated value 411, measured value 411. Compound 75-B: 1 H NMR (400 MHz, CDCl3) δ 3.16-3.13 (m, 1H), 1.98-1.94 (m, 1H), 1.90-1.80 (m, 1H), 1.70-1.58 (m, 4H), 1.56-1.36 (m, 8H), 1.34-1.16 (m, 9H), 1.15-0.96 (m, 7H), 0.95-0.91 (m, 4H), 0.89 (s, 9H), 0.88-0.84 (m, 3H), 0.82 (s, 3H), 0.70-0.60 (m, 4H).LCMS t R = 1.416 min (2 min chromatography, 30-90AB_ELSD), purity 98.0%, C 30 H 51 [M+H-2H2O] + MS ESI calculated value 411, measured value 411. material and method

[0130] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures, for example, as described in WO 2013 / 036835 and WO 2014 / 160480. Where typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, it is understood that other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one of ordinary skill in the art by routine optimization.

[0131] Moreover, as may be clear to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.The selection of suitable protecting groups for certain functional groups and the conditions suitable for protection and deprotection are well known in the art.For example, numerous protecting groups and their introduction and removal are described in TW Greene and PG M Huts, Protecting Groups in Organic Synthesis, 2nd Edition, Wiley, New York, 1991 and the references cited therein.

[0132] The compounds provided herein can be isolated and purified by known standard procedures. Such procedures include (but are not limited to) recrystallization, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The compounds provided herein can be prepared from known or commercially available starting materials and reagents by those skilled in the art of organic synthesis. Exemplary chiral columns available for use in the separation / purification of the enantiomers / diastereomers provided herein include, but are not limited to, CHIRALPAK® AD-10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ, and CHIRALCEL® OK.

[0133] As reported herein 1It will be understood that H-NMR (e.g., for a δ (ppm) region of about 1 to about 4 ppm) is an exemplary interpretation of the NMR spectrum of the compound (e.g., exemplary peak integrations). Exemplary general method for preparative HPLC: Column: Waters RBridge prep 10 μm C18, 19×250 mm. Mobile phase: Acetonitrile, water (NH4HCO3) (30 L water, 24 g NH4HCO3, 30 mL NH3.H2O). Flow rate: 25 mL / min. minutes

[0134] Exemplary general method for analytical HPLC: Mobile phase: A: water (10 mM NH4HCO3), B: acetonitrile; Gradient: 5% to 95% B in 1.6 or 2 min; Flow rate: 1.8 or 2 mL / min; Column: XBridge C18, 4.6 x 50 mm, 3.5 μm, 45 °C. NMDA Augmentation

[0135] NMDA potentiation was assessed using whole-cell patch clamp on any mammalian cell expressing the NMDA receptor. Whole-cell patch clamp of mammalian cells (Ionworks Barracuda (IWB)) The effects of the compounds on the GluN1 / GluN2A glutamate receptors expressed in mammalian cells were examined using the whole-cell patch clamp technique, and the results are shown in Table 1. HEK293 cells were transformed with adenovirus 5 DNA and transfected with cDNA encoding the human GRIN1 / GRIN2A gene. Stable transfectants were selected using the G418 gene and Zeocin resistance gene incorporated into the expression plasmid and selection pressure maintained with G418 and Zeocin in the medium. Cells were cultured in Dulbecco's modified Eagle's medium / nutrient mixture (D-MEM / F-12) supplemented with 10% fetal bovine serum, 100 μg / ml penicillin G sodium, 100 μg / ml streptomycin sulfate, 100 μg / ml Zeocin, 5 μg / ml blasticidin, and 500 μg / ml G418. The effects of test articles were evaluated in an 8-point concentration-response format (4 replicate wells / concentration). All test and control solutions contained 0.3% DMSO and 0.01% Kolliphor® EL (C5135, Sigma). Test article formulations were loaded into 384-well compound plates using an automated liquid handling system (SciClone ALH3000, Caliper Life Sciences). Measurements were performed using the Ion Works Barracuda platform according to this procedure: Electrophysiological procedures: a) Intracellular solution (mM): 50 mM CsCl, 90 mM CsF, 2 mM MgCl2, 5 mM EGTA, 10 mM HEPES. Adjust to pH 7.2 with CsOH. b) Extracellular solution, HB-PS (composition in mM): NaCl, 137; KCl, 1.0; CaCl2, 5; HEPES, 10; glucose, 10; adjust pH to 7.4 with NaOH (refrigerate until use). c) Holding potential: -70 mV, potential during agonist / PAM application: -40 mV. Recording Procedure: a) Extracellular buffer is filled into the wells of the PPC plate (11 μL per well). The cell suspension is pipetted into the wells of the PPC planar electrodes (9 μL per well). b) The whole-cell recording setup is established by patch punching and membrane currents are recorded by a built-in patch clamp amplifier. c) Two recordings (scans) are made: the first during preapplication of the test substance alone (duration of preapplication, 5 min), and the second during preapplication of the test substance and agonist (EC 20 Recordings are made during the simultaneous application of 30 μM L-glutamate and 30 μM glycine) to detect positive modulatory effects of test substances. Test article administration: The first pre-application consisted of the addition of 20 μL of 2× concentrated test article solution at 10 μL / s (total application time of 2 seconds), the second of 20 μL of 1× concentrated test article and agonist. [Table 1-1] [Table 1-2] [Table 1-3] In Table 1, "A" indicates 10-75%, "B" indicates >75%-150% enhancement; "C" indicates >150% enhancement; and "ND" indicates not measurable or not determined. Other embodiments

[0136] In the claims, articles (e.g., "a," "an," and "the") can mean one or more, unless indicated to the contrary or otherwise clear from the context. Unless indicated to the contrary or otherwise clear from the context, a claim or description including "or" between one or more members of a group is deemed to satisfy that one, more than one, or all group members are present in, used in, or otherwise relevant to a given product or process. The invention includes embodiments in which exactly one member of the group is present in, used in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one or all group members are present in, used in, or otherwise relevant to a given product or process.

[0137] Furthermore, the present invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims are introduced into another claim. For example, any claim that is dependent on another claim may be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as a list, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element may be removed from the group. In general, where the invention or an aspect of the invention is referred to as comprising certain elements and / or features, it should be understood that certain embodiments of the invention or an aspect of the invention consist of or consist essentially of such elements and / or features. For purposes of simplicity, those embodiments have not been expressly set forth herein in these exact words. It should also be noted that the terms "comprising" and "containing" are intended to be open and allow for the inclusion of additional elements or steps. Where ranges are given, the endpoints are included. Furthermore, unless otherwise indicated or otherwise clear from the context and understanding of one of ordinary skill in the art, ranges and definitions are not intended to be construed as limiting the scope of the invention or aspects of the invention. Values ​​expressed in units of 1 / 2, 1 / 2, 1 / 4, 1 / 8, 1 / 16, 1 / 16, 1 / 2, 1 / 16 ...16, 1 /

[0138] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any incorporated reference and this specification, this specification shall control. Furthermore, any particular embodiment of the present invention that falls within the scope of the prior art may be expressly excluded from any one or more of the claims. Since such embodiments are deemed known to those skilled in the art, they may be excluded even if the exclusion is not expressly set forth herein. Any particular embodiment of the present invention may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0139] Those skilled in the art will recognize or be able to ascertain, using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the embodiments described herein is not intended to be limited to the above description, but is as set forth in the appended claims. Those skilled in the art will recognize that various changes and modifications to this description may be made without departing from the spirit or scope of the invention as defined in the following claims.

[0140] According to a preferred embodiment of the present invention, for example, the following is provided: (Section 1) Formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 or C 1~6 is alkyl; R 2 is C 1~6 is alkyl, carbocyclyl or heterocyclyl; R 5 is absent or is hydrogen; [ka] represents a single or double bond, where [ka] When is a double bond, the other [ka] is a single bond, and R 5 does not exist, A compound or a pharma- ceutically acceptable salt thereof. (Section 2) R 1 But, C 1~6 Item 2. The compound according to item 1, wherein the compound is alkyl. (Section 3) R 1 But substitution C 1~6 3. The compound according to item 2, wherein the aryl group is alkyl. (Section 4) R 1 But non-substituted C 1~6 3. The compound according to item 2, wherein the aryl group is alkyl. (Section 5) R 1 is methyl (e.g., -CH3, -CF3-CH2OCH3 or -CH(CH3)(CF3)), ethyl or isopropyl. (Section 6) R 1 The compound according to the above item 1, wherein is methyl (eg, -CH3) or ethyl (eg, -CH2CH3). (Section 7) R 2 But, C 1~6 The compound according to the above item 1, which is alkyl or carbocyclyl. (Section 8) R 2 The compound according to the above item 1, wherein is methyl, ethyl, isopropyl or cyclopropyl. (Section 9) R 2 The compound according to the above item 1, wherein is carbocyclyl or heterocyclyl. (Section 10) R 2 Item 10. The compound according to item 9, wherein is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. (Section 11) R 2 10. The compound according to item 9, wherein is an oxygen-containing heterocycle (eg, tetrahydropyran). (Section 12) [ka] Item 3. The compound according to item 1, wherein represents a single bond. (Section 13) The compound of formula (I) has formula (IA) or formula (IB): [ka] Item 3. The compound according to item 1, which is a compound of the formula: (Section 14) The compound of formula (I) may be represented by formula (II): [ka] or a pharma- ceutically acceptable salt thereof. (Section 15) The compound of formula (II) is represented by formula (II-A) or formula (II-B): [ka] Item 15. The compound according to item 14, which is a compound of the formula: (Section 16) The compound of formula (I) may be represented by formula (III): [ka] or a pharma- ceutically acceptable salt thereof. (Section 17) The compound of formula (I) is represented by formula (III-A) or formula (III-B): [ka] Item 17. The compound according to item 16, which is a compound of the formula: (Section 18) The compound of formula (I) may be represented by formula (IV): [ka] or a pharma- ceutically acceptable salt thereof. (Section 19) The compound of formula (I) is represented by formula (IV-A) or formula (IV-B): [ka] 19. The compound according to the above item 18, which is the compound represented by the formula: (Section 20) The compound of formula (I) has the formula (V): [ka] or a pharma- ceutically acceptable salt thereof. (Section 21) The compound of formula (I) has formula (VA) or formula (VB): [ka] 20. The compound according to item 19, which is the compound represented by the formula: (Section 22) The compound of formula (I) [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof. (Section 23) A pharmaceutical composition comprising the compound according to item 1 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier. (Section 24) A method for inducing sedation or anesthesia, comprising administering to a subject an effective amount of the compound described in paragraph 1 above, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof. (Section 25) A method for treating or preventing a disorder described herein, comprising administering to said subject or a method comprising the step of administering to a subject in need of prevention an effective amount of the compound according to item 1 above, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof. (Section 26) 26. The method according to claim 25, wherein the disorder is a gastrointestinal (GI) disorder, such as constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) (e.g. ulcerative colitis, Crohn's disease), structural disorders affecting the GI, anal disorders (e.g. hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas), colon polyps, cancer, colitis. (Section 27) 27. The method according to claim 26, wherein the disorder is inflammatory bowel disease. (Section 28) Item 29. The method according to item 26, wherein the disorder is cancer, diabetes, or a sterol synthesis disorder. A method for treating or preventing a CNS-related condition, comprising administering to a subject in need of said treatment or prevention an effective amount of the compound described in paragraph 1 above, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof. (Section 30) The CNS-related condition is selected from the group consisting of adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder and social phobia), cognitive disorders (including Alzheimer's disease and other forms of dementia), dissociative disorders, eating disorders, mood disorders (including depression (e.g., postpartum depression), bipolar disorder, dysthymic disorder, suicidal ideation), schizophrenia or other psychotic disorders (including schizoaffective disorder), sleep disorders (including insomnia), substance-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including Shank family proteins (e.g., Sh ank3), neurodevelopmental disorders (including Rett syndrome, tuberous sclerosis syndrome), multiple sclerosis, sterol synthesis disorders, pain (including acute and chronic pain), encephalopathy secondary to a medical condition (including hepatic encephalopathy and anti-NMDA receptor encephalitis), seizure disorders (including status epilepticus and monogenic forms of epilepsy, e.g. Dravet's disease), stroke, traumatic brain injury, movement disorders (including Huntington's disease and Parkinson's disease), visual disorders, hearing loss and tinnitus. (Section 31) 30. The method according to claim 29, wherein the disorder is a sterol synthesis disorder.

Claims

[Claim 1] In vivo efficacy.

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