Oxysterols and methods of use thereof

Abstract

To provide compounds useful for preventing and / or treating disorders.SOLUTION: The present invention provides compounds according to formula (I) in the figure and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; where R1, R2, R3, R6, R7, R8 and n are as defined herein. The compounds of the present invention are expected to be useful for 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, formulatability, stability and / or safety as 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 / 189,048, filed July 6, 2015, and U.S. Provisional Application No. 62 / 280,394, filed January 19, 2016, the contents of each of which are incorporated herein by reference in their entirety. [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 C 1~6 R is alkyl; 2 and R 3 Each of 1~6 alkyl or carbocyclyl; or R 2 and R 3together with the carbon atoms to which they are attached form a 3- to 8-membered ring; R 6 is absent or hydrogen; R 7 and R 8 Each of the groups is independently hydrogen, halogen, C 1~6 alkyl or carbocyclyl; or R 7 and R 8 each together with the carbon atom to which they are attached form a 3- to 8-membered ring; or R 2 and R 7 together with the carbon atoms to which they are attached form a 3- to 8-membered ring; n is 1, 2, or 3; [ka] represents a single or double bond, where [ka] When is a double bond, the other [ka] is a single bond; [ka] When one of the groups is a double bond, R 6 does not exist.

[0005] 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., -CHF2, -CH3, -CF3, -CH2OCH3 or -CH2OCH2CH3), ethyl or isopropyl. 1is -CH3. In some embodiments, R 1 is ethyl.

[0006] In some embodiments, R 2 and R 3 Each of 1~6 alkyl or carbocyclyl, or R 2 and R 3 together with the carbon atom to which they are attached form a 3-8 membered ring. In some embodiments, the 3-8 membered ring is a carbocyclyl ring (e.g., cyclopropyl). In some embodiments, R 2 and R 3 Each of 1~6 In some embodiments, R 2 and R 3 Each of is independently hydrogen, methyl (e.g., -CH3, -CF3), ethyl (e.g., -CH2CH3, -CH2CF3), propyl, isopropyl, cyclopropyl, or butyl.

[0007] In some embodiments, R 2 is a substitution C 1~6 In some implementations, In terms of form, R 2 is unsubstituted C 1~6 It is an alkyl.

[0008] In some embodiments, R 2 is hydrogen, methyl (e.g., -CH3, -CF3), ethyl or isopropyl-.

[0009] In some embodiments, R 3 is a substitution C 1~6 In some embodiments, R 3 is unsubstituted C 1~6 It is an alkyl.

[0010] In some embodiments, R 3is methyl (e.g., -CH3, -CF3), ethyl (e.g., -CH2CH3, -CH2CF3), propyl, isopropyl, cyclopropyl or butyl.

[0011] In some embodiments, R 2 and R 3 is hydrogen. In some embodiments, R 2 is hydrogen and R 3 is C 1~6 alkyl (e.g., methyl (e.g., -CH, -CF), ethyl, isopropyl). In some embodiments, R 2 is C 1~6 is alkyl, R 3 is C 1~6 In some embodiments, R 2 and R 3 is -CH3. In some embodiments, R 2 is -CH3, R 3 is -CF3. In some embodiments, R 2 is -CH3, R 3 is ethyl. In some embodiments, R 2 is -CH3, R 3 is isopropyl.

[0012] In some embodiments, [ka] Each of is a single bond.

[0013] In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is present at the alpha position. In some embodiments, R 6 is in the beta position.

[0014] In some embodiments, R 6 does not exist.

[0015] In some embodiments, R 7 and R 8 is hydrogen.

[0016] In some embodiments, n is 1. In some embodiments, n is 1 and R 7 and R 8 is hydrogen.

[0017] In some embodiments, n is 2. In some embodiments, n is 2 and R 7 and R 8 Each of the groups is independently hydrogen, halogen, C 1~6 It is alkyl or carbocyclyl.

[0018] In some embodiments, the compound of formula (I) has the formula (II): [ka] or a pharma- ceutically acceptable salt thereof.

[0019] In some embodiments, the compound of formula (II) has formula (II-A) or formula (II-B): [ka] or a pharma- ceutically acceptable salt thereof.

[0020] In some embodiments, the compound of formula (I) has formula (II-Bi) or formula (II-B-ii): [ka] or a pharma- ceutically acceptable salt thereof.

[0021] In some embodiments, the compound of formula (I) has the formula (II-B-iii): [ka] or a pharma- ceutically acceptable salt thereof.

[0022] In some embodiments, the compound of formula (I) has formula (III): [ka] or a pharma- ceutically acceptable salt thereof.

[0023] In some embodiments, the compound of formula (III) has formula (III-A) or formula (III-B): [ka] or a pharma- ceutically acceptable salt thereof.

[0024] In some embodiments, the compound of formula (III-B) has formula (III-C) or formula (III-D): [ka] or a pharma- ceutically acceptable salt thereof.

[0025] In some embodiments, the compound of formula (III-A) has formula (III-E) or formula (III-F): [ka] or a pharma- ceutically acceptable salt thereof.

[0026] In some embodiments, the compound of formula (III) has formula (III-Aia) or formula (III-Bia): [ka] or a pharma- ceutically acceptable salt thereof.

[0027] In some embodiments, R 1 is methyl (e.g., -CHF2, -CF3, -CH2OCH3 or -CH2OCH2CH3), ethyl or isopropyl.

[0028] In some embodiments, R 2 and R 3 Each of 1~6 alkyl or carbocyclyl, or R 2 and R 3 together with the carbon atoms to which they are attached form a 3- to 8-membered ring.

[0029] In some embodiments, R 2 and R 3 Each of 1~6 It is alkyl or carbocyclyl.

[0030] In some embodiments, R 2 and R 3 Each of is independently hydrogen, methyl (e.g., -CH3, -CF3), ethyl (e.g., -CH2CH3, -CH2CF3), propyl, isopropyl, cyclopropyl, or butyl.

[0031] In some embodiments, R 2 is hydrogen, methyl (e.g., -CH3, -CF3) or ethyl.

[0032] In some embodiments, R 3 is methyl (e.g., -CH3, -CF3), ethyl (e.g., -CH2CH3, -CH2CF3), propyl, isopropyl, cyclopropyl or butyl.

[0033] In some embodiments, the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0034] In some embodiments, the compound of formula (I) has formula (IV): [ka] or a pharma- ceutically acceptable salt thereof.

[0035] In some embodiments, R 1 is methyl (e.g., -CHF2, -CF3, -CH2OCH3 or -CH2OCH2CH3), ethyl or isopropyl.

[0036] In some embodiments, R 2 and R 3 Each of 1~6 alkyl or carbocyclyl, or R 2 and R 3 together with the carbon atoms to which they are attached form a 3- to 8-membered ring.

[0037] In some embodiments, R 2 and R 3 Each of 1~6 It is alkyl or carbocyclyl.

[0038] In some embodiments, R 2 and R 3 Each of is independently hydrogen, methyl (e.g., -CH3, -CF3), ethyl (e.g., -CH2CH3, CH2CF3), propyl, isopropyl, cyclopropyl, or butyl.

[0039] In some embodiments, R 2 is hydrogen, methyl (e.g., -CH3, -CF3) or ethyl.

[0040] In some embodiments, R 3 is methyl (e.g., -CH3, -CF3), ethyl (e.g., -CH2CH3, -CH2CF3), propyl, isopropyl, cyclopropyl, butyl.

[0041] In some embodiments, the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0042] In some embodiments, the compound of formula (I) has formula (V): [ka] or a pharma- ceutically acceptable salt thereof.

[0043] In some embodiments, the compound of formula (I) has the formula (VA): [ka] or a pharma- ceutically acceptable salt thereof.

[0044] In some embodiments, the compound of formula (I) has the formula (VB): [ka] or a pharma- ceutically acceptable salt thereof.

[0045] In some embodiments, the compound of formula (III) has formula (VC) or formula (VD): [ka] or a pharma- ceutically acceptable salt thereof.

[0046] In some embodiments, the compound of formula (I) has the formula (VE): [ka] or a pharma- ceutically acceptable salt thereof.

[0047] In some embodiments, the compound of formula (VE) has the formula (VEi): [ka] or a pharma- ceutically acceptable salt thereof.

[0048] In some embodiments, the compound of formula (I) has formula (VE-ii) or (VE-iii):

[0049] [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0050] In one aspect, provided herein is a pharmaceutical composition comprising a compound described herein, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0051] 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, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0052] In one aspect, provided herein is a method for treating or preventing a disorder described herein, the method comprising administering to a subject in need of such treatment or prevention an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0053] In some embodiments, the disorder is a metabolic disorder.

[0054] 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.

[0055] In some embodiments, the disorder is inflammatory bowel disease.

[0056] In some embodiments, the disorder is cancer, diabetes, or a sterol synthesis disorder.

[0057] In one aspect, a method for treating or preventing a CNS-related condition comprises administering to a subject in need of said treatment or prevention an effective amount of a compound described herein or Provided herein are methods comprising administering 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 (e.g., frontotemporal 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 syndrome, encephalopathy, and the like). These conditions include: neurodevelopmental disorders (including those with mutations in the IL-1 protein (e.g., Shank3)), neurodevelopmental disorders (including Rett syndrome, tuberous sclerosis syndrome), multiple sclerosis, disorders of sterol synthesis, pain (including acute and chronic pain; headaches, e.g., migraine), 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.

[0058] 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).

[0059] In some embodiments, the disorder is a sterol synthesis disorder.

[0060] 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.

[0061] 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

[0062] 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; New 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.

[0063] 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.

[0064] 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.

[0065] 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:

[0066] 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.

[0067] "Aliphatic" refers to an alkyl, alkenyl, alkynyl, or carbocyclyl group, as defined herein.

[0068] "Alkyl" means the radical of a linear or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1~20 In some embodiments, a refers to an alkyl group. The 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 1~8In 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 1~6 Examples 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 1~10Common abbreviations for alkyl include Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2).

[0069] "Alkylene" refers to an alkyl group from which two hydrogens are 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(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, Examples of alkylene groups include, but are not limited to, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-, and the like. When a range or number of carbons is provided for a particular alkylene group, it is understood that the range or number refers to the range or number of carbons in a divalent linear carbon chain. An alkylene group can be substituted or unsubstituted with one or more substituents as described herein.

[0070] "Alkenyl" means an alkyl 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). A radical of a straight or branched chain hydrocarbon group having a double bond ("C 2~20In 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 2~7 In 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 2~4Alkenyl 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.

[0071] "Alkynyl" refers to the radical of a straight-chain or branched-chain hydrocarbon group having 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 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 2~6 In 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 2~4In 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, 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.

[0072] 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 1~10In 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 ("heteroC 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 1~2 In 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 1~10In certain embodiments, the heteroalkyl group is a substituted heteroC 1~10 It is an alkyl.

[0073] "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 ("C 14 "Aryl"; e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused to 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 is reduced by the subtraction. The number of carbon atoms in the aryl ring system is indicated below. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, 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 an aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6~14 In certain embodiments, the aryl group is a substituted C 6~14 It is aryl.

[0074] 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.

[0075] Representative examples of substituted aryl include: [ka] Here, R 56 and R 57 can be hydrogen, and R 56 and R 57At 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.

[0076] 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.

[0077] "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.

[0078] "Heteroaryl" refers to a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., in a cyclic arrangement) in which ring carbon atoms and one to four ring heteroatoms are provided in the aromatic ring system. "Heteroaryl" refers to a radical of a heteroaryl ring system having 6 or 10 pi electrons shared at each heteroatom, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). 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).

[0079] 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.

[0080] 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, azepinyl, oxepinyl, and Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0081] 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.

[0082] "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.

[0083] "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 include carbocyclyl groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), and bicyclo[2.2.2]octanyl (C8). The present invention is not limited to the above. 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")), and 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.

[0084] 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.

[0085] "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 to 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 to 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 and optionally It is substituted, i.e., it is not substituted ("unsubstituted heterocyclyl") or it is 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 a substituted 3-10 membered heterocyclyl.

[0086] 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.

[0087] 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.

[0088] "Nitrogen-containing heterocyclyl" groups include heterocyclic groups having at least one nitrogen atom, such as, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), aza-, cyclohexane ... It refers to 4-7 membered non-aromatic cyclic groups including azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine and N-alkylpiperazines (e.g., N-methylpiperazine). Particular examples include azetidine, piperidone and piperazone.

[0089] "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.

[0090] "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 20is 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.

[0091] "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.

[0092] 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~C 10 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 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.

[0093] "Amino" refers to the -NH2 radical.

[0094] "Substituted amino" refers to a group of the formula -N(R 38 )2, where R 38is 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, 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~C 10 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.

[0095] 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 39 independently 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.

[0096] "Carboxy" refers to the radical -C(O)OH.

[0097] "Cyano" refers to the radical -CN.

[0098] "Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). In certain embodiments, a halo group is fluoro or chloro.

[0099] "Hydroxy" refers to the radical -OH.

[0100] "Nitro" refers to the radical -NO2.

[0101] "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.

[0102] "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.

[0103] "Thioketo" refers to the group =S.

[0104] 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.

[0105] 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 、-SC(=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;

[0106] 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;

[0107] R aa Each occurrence of is independently 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 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;

[0108] 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 6~14aryl and 5- to 14-membered heteroaryl, or two R bb 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;

[0109] 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;

[0110] 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, -NRff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff ) 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 ee , -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 ddThe substituents may be taken together to form =O or =S;

[0111] R ee Each occurrence of is independently 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, 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;

[0112] 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;

[0113] 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(C1~6 Alkyl) + X - , -NH3 + X - , -N(OC 1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6 alkyl), -NH(OH), -SH, -SC 1~6 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), -SO 2N(C 1~6 Alkyl)2, -SO2NH(C 1~6 Alkyl), -SO2NH2, -SO2C 1~6 Alkyl, -SO2OC 1~6 Alkyl, -OSO2C1~6 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 1~6 Alkyl), -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.

[0114] 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 -2Included 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.).

[0115] 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 6~14aryl 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 substituted with R aa , R bb , R cc and R dd is as defined above.

[0116] 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

[0117] The term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. See, for example, Berge et al., J. Pharmacol. 1999, 143:131-135, 1999. Pharmaceutically acceptable salts are described in detail in Journal of the American Chemical Society (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 the 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, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, Pharmaceutically acceptable salts derived from appropriate bases include salts of alkali metals, alkaline earth metals, ammonium salts and N-butyl esters. + (C 1~4Representative 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.

[0118] "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.

[0119] Disease, disorder, and condition are used interchangeably herein.

[0120] 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").

[0121] 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.

[0122] 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.

[0123] As used herein, unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient 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

[0124] Detailed Description of Certain Embodiments of the Invention 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

[0125] In one aspect, the present invention provides a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is C 1~6 R is alkyl; 2 and R 3 Each of 1~6 alkyl or carbocyclyl; or R 2 and R 3 together with the carbon atoms to which they are attached form a 3- to 8-membered ring; R 6 is absent or hydrogen; R 7 and R 8 Each of the groups is independently hydrogen, halogen, C 1~6 alkyl or carbocyclyl; or R 7 and R 8 each together with the carbon atom to which they are attached form a 3- to 8-membered ring; or R 2 and R 7 together with the carbon atoms to which they are attached form a 3- to 8-membered ring; n is 1, 2, or 3; [ka] represents a single or double bond, where [ka] When is a double bond, the other [ka] is a single bond; [ka] When one of the groups is a double bond, R 6 does not exist.

[0126] 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., -CHF2, -CH3, -CF3, -CH2OCH3 or -CH2OCH2CH3), ethyl or isopropyl. 1 is -CH3. In some embodiments, R 1 is ethyl.

[0127] In some embodiments, R 2 and R 3 Each of 1~6 alkyl or carbocyclyl, or R 2 and R 3 together with the carbon atom to which they are attached form a 3-8 membered ring. In some embodiments, the 3-8 membered ring is a carbocyclyl ring (e.g., cyclopropyl). In some embodiments, R 2 and R 3 Each of 1~6 In some embodiments, R 2 and R 3Each of is independently hydrogen, methyl (e.g., -CH3, -CF3), ethyl (e.g., -CH2CH3, -CH2CF3), propyl, isopropyl, cyclopropyl, or butyl.

[0128] In some embodiments, R 2 is a substitution C 1~6 In some embodiments, R 2 is unsubstituted C 1~6 It is an alkyl.

[0129] In some embodiments, R 2 is hydrogen, methyl (e.g., -CH3, -CF3), ethyl or isopropyl-.

[0130] In some embodiments, R 3 is a substitution C 1~6 In some embodiments, R 3 is unsubstituted C 1~6 It is an alkyl.

[0131] In some embodiments, R 3 is methyl (e.g., -CH3, -CF3), ethyl (e.g., -CH2CH3, -CH2CF3), propyl, isopropyl, cyclopropyl or butyl.

[0132] In some embodiments, R 2 and R 3 is hydrogen. In some embodiments, R 2 is hydrogen and R 3 is C 1~6 alkyl (e.g., methyl (e.g., -CH, -CF), ethyl, isopropyl). In some embodiments, R 2 is C 1~6 is alkyl, R 3 is C 1~6 In some embodiments, R 2 and R 3 is -CH3. In some embodiments, R2 is -CH3, R 3 is -CF3. In some embodiments, R 2 is -CH3, R 3 is ethyl. In some embodiments, R 2 is -CH3, R 3 is isopropyl.

[0133] In some embodiments, [ka] Each of is a single bond.

[0134] In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is present at the alpha position. In some embodiments, R 6 is in the beta position.

[0135] In some embodiments, R 6 does not exist.

[0136] In some embodiments, R 7 and R 8 is hydrogen.

[0137] In some embodiments, n is 1. In some embodiments, n is 1 and R 7 and R 8 is hydrogen.

[0138] In some embodiments, n is 2. In some embodiments, n is 2 and R 7 and R 8 Each of the groups is independently hydrogen, halogen, C 1~6 It is alkyl or carbocyclyl.

[0139] In some embodiments, the compound of formula (I) has the formula (II): [ka] or a pharma- ceutically acceptable salt thereof.

[0140] In some embodiments, the compound of formula (II) has formula (II-A) or formula (II-B): [ka] or a pharma- ceutically acceptable salt thereof.

[0141] In some embodiments, the compound of formula (I) has formula (II-Bi) or formula (II-B-ii): [ka] or a pharma- ceutically acceptable salt thereof.

[0142] In some embodiments, the compound of formula (I) has the formula (II-B-iii): [ka] or a pharma- ceutically acceptable salt thereof.

[0143] In some embodiments, the compound of formula (I) has formula (III): [ka] or a pharma- ceutically acceptable salt thereof.

[0144] In some embodiments, the compound of formula (III) has formula (III-A) or formula (III-B): [ka] or a pharma- ceutically acceptable salt thereof.

[0145] In some embodiments, the compound of formula (III-B) has formula (III-C) or formula (III-D): [ka] or a pharma- ceutically acceptable salt thereof.

[0146] In some embodiments, the compound of formula (III-A) has formula (III-E) or formula (III-F): [ka] or a pharma- ceutically acceptable salt thereof.

[0147] In some embodiments, the compound of formula (III) has formula (III-Aia) or formula (III-Bia): [ka] or a pharma- ceutically acceptable salt thereof.

[0148] In some embodiments, R 1 is methyl (e.g., -CHF2, -CF3, -CH2OCH3 or -CH2OCH2CH3), ethyl or isopropyl.

[0149] In some embodiments, R 2 and R 3 Each of 1~6 alkyl or carbocyclyl, or R 2 and R 3 together with the carbon atoms to which they are attached form a 3- to 8-membered ring.

[0150] In some embodiments, R 2and R 3 Each of 1~6 It is alkyl or carbocyclyl.

[0151] In some embodiments, R 2 and R 3 Each of is independently hydrogen, methyl (e.g., -CH3, -CF3), ethyl (e.g., -CH2CH3, -CH2CF3), propyl, isopropyl, cyclopropyl, or butyl.

[0152] In some embodiments, R 2 is hydrogen, methyl (e.g., -CH3, -CF3) or ethyl.

[0153] In some embodiments, R 3 is methyl (e.g., -CH3, -CF3), ethyl (e.g., -CH2CH3, -CH2CF3), propyl, isopropyl, cyclopropyl or butyl.

[0154] In some embodiments, the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0155] In some embodiments, the compound of formula (I) has formula (IV): [ka] or a pharma- ceutically acceptable salt thereof.

[0156] In some embodiments, R 1 is methyl (e.g., -CHF2, -CF3, -CH2OCH3 or -CH2OCH2CH3), ethyl or isopropyl.

[0157] In some embodiments, R2 and R 3 Each of 1~6 alkyl or carbocyclyl, or R 2 and R 3 together with the carbon atoms to which they are attached form a 3- to 8-membered ring.

[0158] In some embodiments, R 2 and R 3 Each of 1~6 It is alkyl or carbocyclyl.

[0159] In some embodiments, R 2 and R 3 Each of is independently hydrogen, methyl (e.g., -CH3, -CF3), ethyl (e.g., -CH2CH3, CH2CF3), propyl, isopropyl, cyclopropyl, or butyl.

[0160] In some embodiments, R 2 is hydrogen, methyl (e.g., -CH3, -CF3) or ethyl.

[0161] In some embodiments, R 3 is methyl (e.g., -CH3, -CF3), ethyl (e.g., -CH2CH3, -CH2CF3), propyl, isopropyl, cyclopropyl, butyl.

[0162] In some embodiments, the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0163] In some embodiments, the compound of formula (I) has formula (V): [ka] or a pharma- ceutically acceptable salt thereof.

[0164] In some embodiments, the compound of formula (I) has the formula (VA): [ka] or a pharma- ceutically acceptable salt thereof.

[0165] In some embodiments, the compound of formula (I) has the formula (VB): [ka] or a pharma- ceutically acceptable salt thereof.

[0166] In some embodiments, the compound of formula (III) has formula (VC) or formula (VD): [ka] or a pharma- ceutically acceptable salt thereof.

[0167] In some embodiments, the compound of formula (I) has the formula (VE): [ka] or a pharma- ceutically acceptable salt thereof.

[0168] In some embodiments, the compound of formula (VE) has the formula (VEi): [ka] or a pharma- ceutically acceptable salt thereof.

[0169] In some embodiments, the compound of formula (I) has formula (VE-ii) or (VE-iii):

[0170] [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof. Pharmaceutical Compositions

[0171] In another aspect, the present invention provides pharmaceutical compositions comprising a pharma- ceutically acceptable carrier and an effective amount of a compound of formula (I).

[0172] 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.

[0173] In one embodiment, with respect to the pharmaceutical composition, the carrier is a parenteral carrier, an oral or a topical carrier.

[0174] The present invention also relates to a compound of formula (I) or a pharmaceutical composition thereof for use as a medicine or medicament.

[0175] 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.

[0176] The pharmaceutical compositions provided herein can be administered by a variety of routes, including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal. Depending on the intended route of delivery, the The compounds provided herein are preferably formulated as injectable compositions, or oral compositions, or as ointments, lotions or patches, all for transdermal administration.

[0177] Compositions for oral administration may take the form of bulk liquid solutions or suspensions or bulk powders. More commonly, however, compositions are provided in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, 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 premeasured, prefilled ampoules or syringes of liquid compositions, or pills, tablets, capsules, and the like 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.

[0178] 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).

[0179] 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.

[0180] 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.

[0181] 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.

[0182] 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).

[0183] For orally administrable, injectable or topically administrable compositions The above-described components are merely representative. Other materials and processing techniques are set forth in Part 8 of Remington's The Science and Practice of Pharmacy, 21st edition, 2005, Publisher: Lippincott Williams & Wilkins (herein incorporated by reference).

[0184] 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.

[0185] The present invention also relates to pharma- ceutically acceptable formulations of the 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 substitutions. 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. Patent No. 5,376,645. In certain embodiments, the formulation comprises hexapropyl-β-cyclodextrin. In a more specific embodiment, the formulation comprises hexapropyl-β-cyclodextrin (10-50% in water).

[0186] The present invention also relates to pharma- ceutically acceptable acid addition salts of the compounds of formula (I).The 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).

[0187] 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.

[0188] Exemplary Formulation 1 - Tablets: A compound of formula (I) or a pharma- ceutically acceptable salt thereof may 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.

[0189] Exemplary Formulation 2 - Capsules: A compound of formula (I) or a pharma- ceutically acceptable salt thereof may 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).

[0190] Exemplary Formulation 3-Solution: The 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 then diluted with water and added with stirring to a total volume of 5 mL. , sufficient water may be added.

[0191] Exemplary Formulation 4 - Tablets: A compound of formula (I) or a pharma- ceutically acceptable salt thereof may 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.

[0192] Exemplary Formulation 5 - Injection: A compound of formula (I) or a pharma- ceutically acceptable salt thereof may be dissolved or suspended in an injectable aqueous medium, which is sterile buffered saline, to a concentration of approximately 5 mg / mL.

[0193] Exemplary Formulation 6 - Tablets: A compound of formula (I) or a pharma- ceutically acceptable salt thereof may 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.

[0194] Exemplary Formulation 7 - Tablets: 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.

[0195] Exemplary Formulation 8 - Tablets: A compound of formula (I) or a pharma- ceutically acceptable salt thereof may 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.

[0196] Exemplary Formulation 9 - Tablets: A compound of formula (I) or a pharma- ceutically acceptable salt thereof may 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.

[0197] Exemplary Formulation 10 - Tablets: A compound of formula (I) or a pharma- ceutically acceptable salt thereof may 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.

[0198] 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.

[0199] 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.

[0200] Transdermal doses are generally similar to or lower than the levels achieved using injected doses. The active ingredient is selected to provide a low blood level.

[0201] 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

[0202] 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, inhibiting or enhancing the function of the NMDA receptor. In certain embodiments, the compounds of formula (I) or pharma- ceutically acceptable salts thereof may act as negative allosteric modulators (NAMs) of NMDA and inhibit the function of the NMDA receptor. In certain embodiments, the present invention, e.g., 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 compound of formula (I) or a pharma- ceutically acceptable salt thereof modulates the function of NMDA but does not act as a negative allosteric modulator (NAM) or a positive allosteric modulator (PAM) of NMDA.

[0203] 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.

[0204] 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.

[0205] Exemplary conditions associated with NMDA modulation include, but are not limited to, gastrointestinal (GI) disorders, 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, and CNS conditions, such as those described herein.

[0206] 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) or pharmacologic salts thereof, may be used to induce sedation or anesthesia. In certain embodiments, the compound of formula (I) or its pharma- ceutically acceptable salt is useful in treating or preventing adjustment disorder, anxiety disorder, cognitive disorder, dissociative disorder, eating disorder, mood disorder, schizophrenia or other psychotic disorder, sleep disorder, substance-related disorder, personality disorder, autism spectrum disorder, neurodevelopmental disorder, sterol synthesis disorder, pain, seizure disorder, stroke, traumatic brain injury, movement disorder and visual disorder, 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).

[0207] 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.

[0208] 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

[0209] In one aspect, a method for treating sterol synthesis disorder 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 deficiency of any enzyme involved in cholesterol biosynthesis lead to accumulation of intermediates and imbalance of biomolecules, resulting in disorders including congenital skeletal deformities, dysmorphic facial features, psychomotor retardation and growth disorders. In one embodiment, sterol synthesis disorder or symptoms of sterol synthesis disorder are sterol synthesis disorder. The present invention can be treated by administering a compound described herein (e.g., an NMDA receptor modulating compound as described herein) to a subject suffering from the above-mentioned disorders. Additional disorders are described below. Smith-Lemli-Opitz syndrome

[0210] 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

[0211] 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

[0212] 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)

[0213] 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)

[0214] Mevalonate kinase deficiency, also called mevalonic aciduria (a more severe form of MKD) or hyperimmunoglobulin D syndrome with periodic fever (HIDS or hyperglobulin Demia) (a more benign form of MKD), causes accumulation of mevalonic acid in the urine as a result of insufficient activity of mevalonate kinase. MKD can result in growth retardation, hypotonia, anemia, hepatosplenomegaly, dysmorphic features, mental retardation, and general failure to thrive. Mevalonic aciduria is a condition that can cause physical, mental, and emotional problems. It is characterized by delayed physical and mental development, growth retardation, recurrent episodes of fever accompanied by vomiting and diarrhea, enlarged liver, spleen and lymph nodes, microcephaly (small head size), cataracts, low muscle tone, 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)

[0215] 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

[0216] 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

[0217] 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

[0218] 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 state. Total cholesterol and low-density cholesterol and 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., representing 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. Changes in the levels of 24S-OHC and 7β-hydroxycholesterol correlate with the levels of phenylalanine, and the levels of 27S-hydroxycholesterol may correlate with the levels of 25-hydroxyvitamin D in subjects with phenylketonuria. Abbreviations

[0219] PCC: pyridinium chlorochromate; t-BuOK: potassium tert-butoxide; 9-BBN: 9-borabicyclo[3.3.1]nonane; Pd(t-Bu3P)2: bis(tri-tert-butylphosphine)palladium(0); AcCl: acetyl chloride; i-PrMgCl: isopropylmagnesium chloride; TBSCl: tert-butyl(chloro)dimethylsilane; (i-PrO)4Ti: titanium tetraisopropoxide; BHT: 2,6-di-t-butyl-4-methylphenoxide; Me: methyl; Ph: phenyl; Et: ethyl; Bz: benzoyl; DCC: dicyclohexylcarbodiimide; DCM: dichloromethane; DMAP: 4-dimethylaminopyridine; DMP: Dess-Martin periodinane; EtOAc: ethyl acetate; TEA: triethylamine; AlaOH: alanine; Boc: t-butoxycarbonyl. Py: pyridine; TBAF: tetra-n-butylammonium fluoride; THF: tetrahydrofuran; TMS: trimethylsilyl; MAD: methylaluminum bis(2,6-di-t-butyl-4-methylphenoxide); Na2SO4: sodium sulfate; Na2S2O3: sodium thiosulfate; PE: petroleum ether; MeCN: acetonitrile; MeOH: methanol; Py: pyridine, Boc: t-butoxycarbonyl; MTBE: methyl tert-butyl ether. EXAMPLES

[0220] In order that the invention described herein may be more fully understood, the following examples are set forth. 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.

[0221] The stereochemistry assigned herein (e.g., the assignment of "R" or "S" to the C25 or C27 positions of a steroid) may be tentatively (e.g., randomly) assigned. For example, the C25 position may be depicted in the "R" configuration when the absolute configuration is "S". Also, the C25 position may be depicted in the "S" configuration when the absolute configuration is "R".

[0222] Example 1. Synthesis of Compound 1 [ka] Step 1. To a solution of reactant A1 (700 mg, 1.73 mmol) in anhydrous CHCl (5 mL) was added Dess-Martin reagent (1.09 g, 2.59 mmol) in small portions at 0° C. The reaction mixture was stirred at 25° C. for 3 h. The mixture was quenched with saturated aqueous NaHCO3 / Na2S2O3 (1:3, 15 mL) and extracted with EtOAc (2×50 mL). The organic phase was then washed with brine (50 mL), dried over Na2SO4, and concentrated to give A2 as a crude residue (700 mg), which was used directly in the next step without further purification. Step 2. To a solution of BHT (2.29 g, 10.4 mmol) in toluene (10 mL) was added a solution of AlMe3 (2.61 mL, 5.22 mmol) (2 M in toluene) at 25 °C. The resulting mixture was stirred at 25 °C for 1 h, after which a solution of A2 (700 mg, 1.74 mmol) in toluene (5 mL) was added at -78 °C under nitrogen. The mixture was stirred for an additional 30 min, after which MeMgBr (3.0 M in Et2O, 1.74 mL, 5.22 mmol) was added dropwise at -78 °C. The reaction mixture was stirred at this temperature for 3 h and then quenched with saturated aqueous NH4Cl (30 mL) at -78 °C. The resulting suspension was filtered and the filter cake was washed with EtOAc (2 x 50 mL). The combined organic phases were dried over Na2SO4, concentrated and purified by silica gel (PE / EtOAc = 10 / 1 to 8 / 1) to give compound 1 (120 mg, 17%) as an off-white solid. 1HNMR (400 MHz, CDCl3) δ5.30 (d, J = 3.6 Hz, 1H), 2.40-2.30 (m, 1H),1.99-1.98(m, 3H), 1.70-1.57(m, 4H),1.46-1.17 (m, 28H), 1.11-0.92 (m, 8H), 0.67 (s,3H). LCMS Rt=1.503 min (2 min chromatography, 10-80AB), C 28 H 49 O2[M+H] + MS ESI calcd for 417, C 28 H 45 [M-2H2O+H] + The actual measured value was 381.

[0223] Example 2. Synthesis of Compounds 2 and 3 [ka] Step 1. To a solution of compound 1 (55 mg, 0.131 mmol) in EtOAc (10 mL) was added Pd / C (50 mg). The reaction mixture was stirred under hydrogen (50 psi) at 50° C. for 12 h, after which it was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel (PE / EtOAc=10 / 1) to give both compound 2 (5 mg, 9%) and compound 3 (47.8 mg, 87%) as off-white solids, respectively. Compound 2: 1 HNMR(400 MHz, CDCl3) δ 1.96 (d, J = 12.4 Hz, 1H), 1.80-1.62 (m,1H),1.60-1.57(m, 3H),1.46-1.24 (m, 28H), 1.21-0.92 (m, 10H), 0.9 0 (s, 3H), 0.70-0.64 (m, 4H). LCMS Rt=1.568 min (2 min chromatogram) Fee, 10-80AB), C 28 H 51 O2[M+H] + MS ESI calcd for 419, C 28 H 47[M-2H2O+H] + The actual value was 383. Compound 3: 1 HNMR(400 MHz, CDCl3) δ 1.98-1.79 (m, 5H),1.75-1.57 (m, 2H),1.55-0.98 (m,34H) ,0.96 (s, 3H), 0.91 (d, J = 8.4 Hz, 3H), 0.64 (s, 3H). LCMS Rt = 1.590 min (2 min chromatography, 10-80AB), C 28 H 51 O2[M+H] + MS ESI calcd for 419, C 28 H 47 [M-2H2O+H] + Actual measured value: 383

[0224] Example 3. Synthesis of Compounds 4, 5, and 6 [ka] Step 1. A mixture of propiolic acid B1 (20 g, 285 mmol) in 40% HBr (150 mL) was stirred at 110° C. for 2 h. The mixture was cooled in ice water. The precipitated solid was filtered off and washed with excess water to give B2 (25 g, 58%) as a brown solid. 1 HNMR(400 MHz, CDCl3) δ 9.69 (br.s., 1H), 7.76(d, J = 14.4 Hz, 1H),6.54(d, J = 13.6 Hz, 1H). Step 2. To a suspension of B2 (8.5 g, 56.3 mmol) in MeOH (15 mL) was added 98% H2SO4 (2.80 g, 28.1 mmol). The mixture was stirred at 25° C. for 24 h. The reaction mixture was evaporated in vacuum. The distillate was washed with water (20 mL). The organic layer was separated and dried over Na2SO4 to give B3 (7 g, 75%) as a colorless oil. 1 HNMR(400 MHz, CDCl3) δ 7.61 (d, J = 14.0Hz, 1H), 6.53(d , J = 14.0 Hz, 1H), 3.76 (s, 3H). Step 3. To a suspension of Ph3PMeBr (67.5 g, 189 mmol) in anhydrous THF (300 mL) under N2, t-BuOK (21.2 g, 189 mmol) was added. After stirring at 60 °C for 30 min, A3 (20 g, 63.1 mmol) was added. The resulting mixture was stirred at 60 °C for 4 h. The reaction mixture was poured into ice water (500 mL) and extracted with EtOAc (2 x 500 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc = 15 / 1) to give A4 (18 g, 91%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ5.39-5.32 (m, 1H), 4.85(s, 1H), 4.71 (s,1H),3.59-3.47 (m, 1H), 2.36-2.17 (m, 2H), 2.07-1.94(m,2H),1.89-1.65 (m, 9H), 1.60-1.39 (m,6H), 1.26-0.92 (m, 8H), 0.59 (s, 3H). Step 4. To a solution of A4 (18 g, 57.2 mmol) in anhydrous DCM (150 mL) was added Ac2O (8.75 g, 85.8 mmol) and DMAP (13.9 g, 114 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with water (200 mL) and extracted with DCM (3 x 150 mL). The combined organic layers were washed with saturated NaHCO3 (150 mL) and brine (150 mL), dried over anhydrous Na2SO4, filtered and concentrated to give A5 (20 g, 99%) as an off-white solid. Step 5. To a solution of A5 (30 g, 84.1 mmol) in anhydrous THF (150 mL) at 30° C. under nitrogen atmosphere was added 9-BBN (0.5 M in THF, 185 mL, 92.5 mmol). The mixture was stirred at 75° C. for 3 h. The reaction mixture was cooled to 30° C. and (E)-methyl 3-bromoacrylate (15.2 g, 92.5 mmol), CsF (25.5 g, 168 mmol) and Pd(t-Bu3P)2 (4.55 g, 8.40 mmol) were added. The resulting mixture was stirred at 75° C. for 16 h. The reaction was cooled, quenched with water (300 mL) and extracted with EtOAc (3×300 mL). The combined organic layers were dried over Na2SO4, filtered through a silica gel pad and concentrated. The residue was triturated from MeOH to give A6 (20 g, 54%) as an off-white solid. 1 HNMR(400 MHz, CDCl3) δ 7.00-6.90 (m, 1H), 5.81(d, J =15.6 Hz, 1H), 5.37 (d, J = 4.5 Hz, 1H),4.66-4.53 (m,1H), 3.73 (s, 3H), 2.36-2.24(m, 3H), 2.03 (s, 3H), 2.00-1.79 (m,6H),1.65-1.38 (m, 8H), 1.34-1.05 (m, 6H),1.0 1 (s, 3H), 0.95 (d, J = 6.5 Hz,3H), 0.69(s, 3H). Step 6. To a suspension of A6 (20 g, 45.1 mmol) in anhydrous MeOH (250 mL) was added AcCl (2.82 g, 36.0 mmol). The mixture was stirred at 25° C. for 16 h. The reaction mixture was concentrated to remove most of the MeOH, diluted with EtOAc (500 mL), washed with saturated NaHCO3 (500 mL), brine (300 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc / DCM=8 / 1 / 1) to give A7 (12 g, 67%) as an off-white solid. Step 7. To a solution of A7 (12 g, 29.9 mmol) in THF (150 mL) was added 5% Pt / C (2 g). The mixture was degassed and purged with H2 several times and stirred under a H2 balloon at 25 °C for 4 h. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated to give A8 (12 g, 100%) as an off-white solid. 1 HNMR (400 MHz, CDCl3) δ 5.34 (d, J =5.0Hz, 1H), 3.66 (s, 3H),3.57-3.45(m, 1H), 2.33-2.21 (m, 4H), 2.05-1.65 (m,7H),1.48-1.32 (m, 6H),1.31-0.88 (m,17H), 0.67 (s, 3H). Step 8. To a solution of A8 (27 g, 67.0 mmol) in DCM (300 mL) was added DMP (85.2 g, 201 mmol) at 25° C. The reaction was stirred at 25° C. for 1 h. The reaction was stirred at 25° C. for 1 h. The mixture was poured into saturated Na2S2O3 (400 ml) at 0° C. and extracted with EtOAc (3×300 mL). The combined organic layers were washed with saturated NaHCO3 (2×250 mL), brine (200 mL), dried over Na2SO4, filtered and concentrated in vacuo to give A9 (27 g, crude) as an oil, which was used directly for the next step without further purification. Step 9. To a solution of BHT (88.8 g, 403 mmol) in toluene (250 mL) was added AlMe3 (100 mL, 201 mmol, 2 M in toluene) dropwise below 25 °C. The solution was stirred at 25 °C for 1 h. A solution of A9 (27 g, 67.3 mmol) in toluene (250 mL) was added dropwise at -78 °C. After stirring at -78 °C for 1 h, MeMgBr (67.0 mL, 201 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 solution (400 mL) at -78 °C. After stirring at 25 °C for 0.5 h, the resulting mixture was filtered and the filtrate was washed with EtOAc. Extraction was performed (3×300 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=5 / 1) to give the product (18.5 g, 66%), of which 70 mg was recrystallized (PE / EtOAc=10 mL / 2 mL) to give A27 (67 mg) as an off-white solid. A27: 1 HNMR(400MHz, CDCl3) δ5.30-5.28 (m, 1H), 3.65(s, 3H), 2.40-0.9 1 (m, 37H), 0.66 (s, 3H). LCMS Rt=1.562 min (2 min chromatography, 10-80AB), C 27 H 43 O2[M+H-H2O] + MS ESI calculated value 399, found value 399. Step 10. To a solution of LiAlH4 (6.11 g, 161 mmol) in THF (135 mL) was added dropwise a solution of A27 (27 g, 64.8 mmol) in THF (135 mL) at 0 °C. The mixture was stirred at 25 °C for 1 h. H2O (100 mL) was added at 0 °C. The reaction mixture was filtered and washed with THF (2 x 100 mL). The filtrate was concentrated in vacuo to give the crude product, which was washed with EtOAc (100 mL) to give compound 4 (25 g, 100%), and 30 mg of the product was recrystallized (EtOAc, 3 mL) to give compound 4 (27 mg) as an off-white solid. Compound 4: 1 HNMR (400 MHz, CDCl3) δ 5.31-5.29 (m,1H),3.70-3.60(m, 2H), 2.43-2 .40 (m, 1H), 2.20-0.90 (m, 37H), 0.67 (s,3H). LCMS Rt=1.402min(2 minutes, 10-80AB), C 26 H 45 O2[M+H] + MS ESI calculated value 389, C 26 H 43 The measured value of O[M+H-H2O] is 371. Step 11. To a solution of compound 4 (18 g, 46.3 mmol) in DCM (180 mL) was added DMP (58.5 g, 138 mmol) at 0° C. The reaction was stirred at 25° C. for 1 h. The mixture was poured into saturated Na2S2O3 (100 mL) at 0° C. The mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with saturated NaHCO3 (2×150 mL), 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=5 / 1) to give A10 (13 g, 73%) as an off-white solid. 1 HNMR(400MHz,CDCl3) δ 9.76 (t, J = 1.8Hz, 1H), 5.33-5.27 (m, 1H),2.46-2.31 (m, 3H), 2.10-0.72 (m, 34H), 0.67 (s, 3H). Step 12. To a solution of A10 (10 g, 25.8 mmol) in THF (100 mL) was added MeMgBr (51 mL, 154 mmol) at 0° C. under N2. The reaction was stirred at 25° C. for 1 h. The reaction was quenched with saturated NH4Cl (30 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (50 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 A11 (4.1 g, 40%) as an off-white solid. 1 HNMR(400MHz, CDCl3) δ 5.30-5.29 (m, 1H),3.81-3.77 (m, 1H), 2.43-2.39(m,1H),1.99-0.76 (m, 40H), 0.67 (s, 3H). Step 13. The mixture of A11 (400 mg, 0.993 mmol) was purified by SFC separation (column: Chiralpak AD 250×30 mm ID, 5 μm; mobile phase: supercritical CO2 / MeOH+NH3H2O=55 / 45; flow rate: 60 ml / min; wavelength: 220 nm) to give compound 5 (peak 1,120 mg, 30%) as an off-white solid and compound 6 (peak 2,150 mg, 38%) as an off-white solid. Compound 5: 1 HNMR(400MHz,CDCl3) δ 5.32-5.27 (m, 1H),3.85-3.72 (m, 1H), 2.45- 2.40 (m, 1H), 2.06-1.91 (m, 3H), 1.88-1.65(m, 3H),1.54-1.33 (m, 12H), 1.32-0.87 (m, 22H), 0.68 (s, 3H). LCMS Rt=1.267 min (2 min chromatography, 30-90AB), C 27 H 47 O2[M+H] + MS ESI calcd for 403, C 27 H 45 O[M-H2O+H] + The actual measured value was 385. Compound 6: 1 HNMR (400 MHz, CDCl3) δ 5.33-5.27 (m,1H),3.84-3.75(m, 1H), 2.45-2 .40 (m, 1H), 2.06-1.92 (m, 3H), 1.89-1.64(m, 3H),1.56-0.79 (m, 34H), 0.67 (s, 3 H). LCMS Rt=1.262 min (2 min chromatography, 30-90AB), C 27 H 47 O2[M+H] + MS ESI calcd for 403, C 27 H 45 O[M-H2 O+H] + The actual measured value was 385.

[0225] Example 4. Synthesis of Compounds 7 and 8 [ka] Step 1. To a solution of A11 (3.6 g, 8.94 mmol) in DCM (40 mL) was added DMP (11.3 g, 26.8 mmol) at 0° C. The reaction was stirred at 25° C. for 1 h. The mixture was poured into saturated Na2S2O3 (60 ml) at 0° C. and extracted with EtOAc (3×50 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (2×50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column (PE / EtOAc=15 / 1) to give A13 (1.4 g, 39%) as an off-white solid. 1 HNMR(400 MHz, CDCl3) δ 5.33-5.31 (m,1H),2.50-2.30 (m, 3H), 2.16 (s,3H),2.02-0.94 (m, 34 H), 0.69 (s, 3H). Step 2. To a solution of A13 (288 mg, 0.718 mmol) in anhydrous THF (10 mL) at −10° C. under N2, EtMgBr (3 M in diethyl ether, 1.43 mL, 4.30 mmol) was added dropwise. The mixture was stirred at 25° C. for 3 h. The mixture was quenched with saturated NH4Cl (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with DCM to give A14 (105 mg, 34%) as an off-white solid. Step 3. A14 (105 mg, 0.244 mmol) was separated by SFC (column: Chiralpak AD 250×30 mm ID, 5 μm; mobile phase: supercritical CO2 / EtOH+NH3H2O=70 / 30; flow rate: 60 ml / min; wavelength: 220 nm) to give compound 7 (peak 1, 21.4 mg, 28%) as an off-white solid and compound 8 (peak 2, 12.4 mg, 16%) as an off-white solid. Compound 7: 1HNMR (400 MHz, CDCl3) δ 5.32-5.28 (m, 1H),2.45-2.40(m, 1H),2.04-1 .93 (m, 3H), 1.81-1.65 (m, 3H), 1.52-0.79(m, 39H), 0.68 (s, 3H). LCMS Rt = 1.378 min (2 min chromatography, 30-90AB), C 29 H 51 O2[M+H] + MS ESI calcd for 431, C 29 H 47 [M+H-2H2O] + The actual measured value was 395. Compound 8: 1 HNMR (400 MHz, CDCl3) δ 5.32-5.28 (m, 1H),2.45-2.40(m, 1H),2.05-1 .94 (m, 3H), 1.88-1.63 (m, 4H), 1.52-0.83(m, 38H), 0.68 (s, 3H). LCMS Rt = 1.374 min (2 min chromatography, 30-90AB), C 29 H 51 O2[M+H] + MS ESI calcd for 431, C 29 H 47 [M+H-2H2O] + The actual measured value was 395.

[0226] Example 5. Synthesis of Compounds 9 and 10 [ka] Step 1. To a solution of A13 (500 mg, 1.24 mmol) in anhydrous THF (5 mL) at 0° C. under N2, i-PrMgCl (2 M in THF, 6.2 mL, 12.3 mmol) was added dropwise. The reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was cooled to 0° C., quenched with saturated NH4Cl (10 mL), and extracted with EtOAc (3×10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (DCM / acetone=500 / 1) to give A16 (160 mg, 29%) as an off-white solid. Step 2. A16 (100 mg, 0.224 mmol) was separated by SFC (column: Chiralpak AD 250×30 mm ID, 5 um; mobile phase: supercritical CO2 / EtOH+NH3H2O=65 / 35; flow rate: 60 ml / min; wavelength: 220 nm) to give compound 9 (peak 1, 26.2 mg, 26%) as an off-white solid and compound 10 (peak 2, 18.8 mg, 19%) as an off-white solid. Compound 9: 1 HNMR (400 MHz, CDCl3) δ 5.33-5.27 (m, 1H),2.45-2.40(m,1H), 2.06-1 .92 (m, 3H), 1.88-1.64 (m, 5H), 1.52-0.78(m, 39H), 0.68 (s, 3H). LCMS Rt = 1.444 min (2 min chromatography, 30-90AB), C 30 H 53 O2[M+H] + MS ESI calculated value: 445, C 30 H 49 [M+H-2H2O] + The actual measured value was 409. Compound 10: 1 HNMR(400 MHz, CDCl3) δ 5.32-5.28 (m, 1H),2.45-2.40(m, 1H),2.05- 1.93 (m, 3H), 1.88-1.65 (m, 5H), 0.84-1.52(m, 39H), 0.68 (s, 3H). LCMS R t=1.442 min (2 min chromatography, 30-90AB), C 30 H 53 O2[M+H] + MS ESI calculated value: 445, C 30 H 49 [M+H-2H2O] + Actual value: 409.

[0227] Example 6. Synthesis of Compounds 11 and 12 [ka] Step 1. To a solution of A13 (300 mg, 0.748 mmol) in THF (5 mL) was added TMSCF3 (106 mg, 0.748 mmol) at 25 °C. The reaction was stirred at 25 °C for 1 h. TBAF (271 mg, 1.04 mmol) was added at 25 °C. The reaction was poured into water and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with saturated NaHCO3 (2 x 20 mL), brine (20 mL) and Na2 Drying over SO4, filtering and concentrating in vacuo afforded A18 (100 mg) as an off-white solid. Step 2. A18 (100 mg. 212 μmol) was purified by SFC separation (column: Chiralpak AD 250×30 mm ID, 5 μm; mobile phase: supercritical CO2 / MeOH+NH3H2O=70 / 30; flow rate: 60 ml / min; wavelength: 220 nm) to give compound 11 (peak 1, 25.6 mg, 26%) and compound 12 (peak 2, 30 mg, 30%) as off-white solids. Compound 11: 1 HNMR (400 MHz, CDCl3) δ 5.33-5.28 (m, 1H),2.45-2.40(m, 1H), 2.06 -1.93 (m, 3H), 1.90-1.61 (m, 6H), 1.56-1.38(m, 9H),1.35 (s, 3H), 1.32-0.82 (m, 19H), 0.68 (s, 3H). LCMS Rt=1.327 min (2 min chromatography, 3 0-90AB), C 28 H 44 F3O[M-H2O+H] + MS ESI calculated value 453, found value 453. Compound 12: 1 HNMR(400 MHz, CDCl3) δ 5.34 - 5.28 (m, 1H),2.45 - 2.40 (m, 1H), 2.06- 1.92 (m, 3H), 1.90 -1.66 (m, 5H), 1.56 - 1.33 (m,13H), 1 .31 - 0.87 (m, 19H), 0.68 (s, 3H). LCMS Rt=1.320 min (2 min chroma topography, 30-90AB), C 28 H 44 F3O[M-H2O+H] + MS ESI calculated value 453, measured value 453.

[0228] Example 7. Synthesis of Compounds 13 and 14 [ka] Step 1. To a solution of A10 (400 mg, 1.03 mmol) in THF (5 mL) was added TMSCF3 (365 mg, 2.57 mmol) at 25 °C. The mixture was stirred at 25 °C for 1 h. TBAF (806 mg, 3.09 mmol) was added. The mixture was stirred at 25 °C for 1 h. The mixture was poured into water (30 mL), washed with saturated brine (2 × 20 mL), dried over Na2SO4, and concentrated in vacuo to give A20 (190 mg, 40%) as an off-white solid. 1HNMR(400 MHz, CDCl3) δ 5.33-5.28 (m, 1H),4.00-3.85 (m, 1H),2.50-2.35(m,1H), 2.11-1.93 (m, 4H), 1.89-1.61 (m , 5H),1.53-1.35 (m, 8H), 1.31-1.05 (m,11H), 1.01 (s, 9H), 0.68 (s, 3H). S Rt = 1.301 min (2 min chromatography, 30-90AB), C 27 H 42 F3O[M-H2O+H] + MS ESI calculated value 439, measured value 439. Step 2. A20 (190 mg, 0.416 mmol) was purified by SFC (column: Chiralpak AD 250×30 mm ID, 5 um; mobile phase: supercritical CO2 / MeOH+NH3H2O=65 / 35; flow rate: 60 ml / min; wavelength: 220 nm) at 25° C. to give compound 13 (peak 1, 38.4 mg, 20%) and compound 14 (peak 2, 47.6 mg, 25%) as off-white solids. Compound 13: 1 HNMR (400 MHz, CDCl3) δ 5.34 - 5.27 (m, 1H),3.98-3.84 (m, 1H), 2.45-2.40 (m, 1H), 2.08 - 1.92 (m, 4H),1.89 - 1.64 (m,6H), 1.53 - 1.36 (m, 7H), 1.33 - 1.21 (m, 3H), 1.21 - 1.08 (m, 7H),1.07 - 0.90(m, 10H), 0.68 (s, 3H). LCMS Rt = 1.302 min (2 min chromatography, 30-90AB), C 27 H 44 F3O2[M+H] + MS ESI calcd for 457, C 27 H 42 F3O[M+H-H2O] + The actual value was 439. Compound 14: 1HNMR(400MHz,CDCl3)δ 5.34-5.28 (m, 1H), 3.95-3.89 (m, 1H), 2.45-2.40 (m,1H),2.06-1.92(m, 4H), 1.89-1.59 (m, 7H),1.54-1.34 (m, 8H), 1.32-1.21 (m, 2H),1.20-1.05(m,8H), 1.04-0.90 (m, 8H), 0.68(s, 3H). LCMS Rt=1.299 min (2 min chromatography, 30-90AB), C 27 H 44 F3O2[M+H] + MS ESI calcd for 457, C 27 H 42 F3O[M+H-H2O] + The actual measured value was 439.

[0229] Example 8. Synthesis of Compound 17 [ka] Step 1. To a solution of A27 (500 mg, 1.20 mmol) and (i-PrO)4Ti (341 mg, 1.20 mmol) in anhydrous THF (10 mL) at 25 °C under N2, EtMgBr (3 M in diethyl ether, 1.39 mL, 4.19 mmol) was added dropwise. The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with brine (15 mL), diluted with EtOAc (20 mL), filtered through a celite pad, and the filtrate was extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc = 20 / 1) to give compound 17 (220 mg, 44%) as an off-white solid. 1 HNMR(400 MHz, CDCl3) δ 5.33-5.27 (m, 1H),2.50-2.40 (m,1 H), 2.06-1.92 (m, 3H), 1.88-1.63 (m, 5H),1.54-1.34 (m, 10H),1.29-0.90 (m, 19H), 0.76-0.65 (m, 5H), 0.47-0.40 (m, 2H). LCMS Rt=1.294 min (2 min chromatography, 30-90AB), C 28 H 47 O2[M+H] + MS ESI calculated value: 415, C 28 H 45 O[M+H-H2O] + The actual measured value was 397.

[0230] Example 9. Synthesis of Compounds 18, 19, and 20 [ka] Step 1. To a solution of A8 (1.4 g, 3.47 mmol) in DCM (20 mL) was added DMP (2.94 g, 6.94 mmol) at 25° C. Stirred for 2 h. The mixture was poured into saturated Na2S2O3 (100 ml) at 0° C. and extracted with EtOAc (2×100 mL). The combined organic layers were washed with saturated NaHCO3 (2×80 mL), brine (100 mL), dried over Na2SO4, and concentrated in vacuo to give A9 (1.5 g, crude) as an off-white solid. Step 2. To a solution of BHT (4.93 g, 22.4 mmol) in toluene (20 mL) was added dropwise AlMe3 (5.60 mL, 2 M in toluene, 11.2 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 1.5 h. A solution of A9 (1.5 g, 3.74 mmol) in toluene (20 mL) was added at −70° C. The resulting mixture was stirred at −70° C. for 1 h. EtMgBr (3.73 mL, 3.0 M in diethyl ether, 11.2 mmol) was added at −70° C. The reaction mixture was stirred at −70° C. for another 1 h. The reaction was quenched with NH4Cl (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (100 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography eluting with PE / EtOAc=10 / 1 to give A30 (600 mg, 35%) as a white solid. 1 HNMR(400 MHz, CDCl3) δ 5.31-5.26 (m, 1H), 3.67(s, 3H), 2.41-2.19(m,3H),2.07-1.91 (m, 3H), 1.88-1.61 (m, 5H), 1.55-1 .33 (m,11H), 1.31-1.01 (m, 10H), 1.00-0.80(m, 7H), 0.67 (s, 3H). Step 3. To a solution of A30 (550 mg, 1.27 mmol) in THF (5 mL) was added MeLi (3.17 mL, 5.08 mmol) at -70 °C. The mixture was stirred at -70 °C for 10 min. The reaction was quenched with saturated NH4Cl (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The mixture was combined with another batch synthesized from 50 mg of starting material. The residue was purified by silica gel chromatography (PE / EtOAc = 10 / 1) to give compound 18 (270 mg, 49% yield) as a white solid. 1 HNMR(400 MHz, CDCl3) δ 5.28 (d, J = 5.0 Hz, 1H), 2.36(d, J= 13.1 Hz, 1H), 2.08-1.91 (m, 3H), 1.89-1.69(m, 3H), 1.65-1.60 (m, 3H),1.51-1.32 (m, 8H), 1.30-1.17 (m, 11H), 1.15-1.01 (m,8H), 0.99-0.81 (m, 9H), 0.68 (s, 3H). LCMS Rt=1.372 min (2 min chromatography, 30-90AB), C 29 H 51 O2[M+H] + MS ESI calcd for 431, C 29 H 47 [M+H-2H2O] + The actual measured value was 395. Step 4. To a solution of compound 18 (200 mg, 0.464 mmol) in EtOAc (10 mL) was added Pd / C (100 mg) at 25° C. The mixture was stirred under H2 at 55° C. for 12 h. The reaction mixture was filtered and the filter cake was washed with EtOAc (2×40 mL). The mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography eluting with PE / EtOAc=10 / 1 to give compound 19 (6.6 mg) and compound 20 (10.2 mg) as off-white solids. Compound 19: 1 HNMR (400 MHz, CDCl3) δ 2.02-1.95 (m,1H),1.94-1.72 (m, 4H),1.52 -1.31 (m, 14H), 1.27-1.16 (m, 14H),1.14-0.99 (m, 7H), 0.97 (s, 3H),0.95-0.89 (m , 6H), 0.65 (s, 3H). LCMS Rt=1.432 min (2 min chromatography, 30-90AB), C 29 H 53 O2[M+H] + MS ESI calculated value: 433, C 29 H 49 [M+H-2H2O] + The actual measured value was 397. Compound 20: 1HNMR (400 MHz, CDCl3) δ 1.96 (d, J = 12.5 Hz,1H),1.86-1.75(m, 1 H), 1.58-1.50 (m, 5H), 1.49-1.29 (m, 10H),1.21 (s, 13H), 1.13-0.95 (m,8H), 0.94 -0.84 (m, 7H), 0.82 (s, 3H), 0.64 (s, 4H). LCMS Rt=1.431 min (2 min Chromatography, 30-90AB), C 29 H 53 O2[M+H] + MS ESI calculated value: 433, C 29 H 49 [M+H-2H2O] + The actual measured value was 397.

[0231] Example 10. Synthesis of Compound 22 [ka] Step 1. To a solution of A7 (3 g, 7.48 mmol) in THF (30 mL) was added Pd / C (10%, 600 mg). The mixture was degassed and purged with H2 three times. The resulting mixture was stirred under H2 at 25 °C for 16 h. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated to give A32 (3 g, 99%) as an off-white solid. 1 HNMR(400 MHz, CDCl3) δ 3.66 (s, 3H), 3.63-3.53(m, 1H),2.34- 2.18 (m, 2H), 1.99-1.91 (m, 1H), 1.82-1.62(m, 5H), 1.56-1.43 (m,3H), 1.42-1.18 (m, 10H), 1.14-0.77 (m, 15H), 0.68-0.57 (m,4H). Step 2. To a solution of A32 (3 g, 7.41 mmol) in DCM (30 mL) was added PCC (3.19 g, 14.8 mmol) and silica gel (4 g, 66.6 mmol) at 25° C. The mixture was stirred at 25° C. for 1.5 h. The mixture was filtered. The filtrate was concentrated in vacuum and purified by column chromatography on silica gel (PE / EtOAc=50 / 1 to 10 / 1) to give A33 (2.4 g) as an off-white solid. 1 HNMR(400MHz, CDCl3) δ 3.66 (s, 3H), 2.44-2.19(m, 5H), 2.13-1.94 (m, 3H), 1.89-1.64 (m, 3H), 1.53-0.82 (m,24H), 0.76-0.66(m, 4H). Step 3. To a solution of BHT (7.88 g, 35.7 mmol) in toluene (25 mL) was added AlMe3 (8.9 mL, 17.8 mmol, 2 M in toluene) at 0° C. under N2. The mixture was stirred at 25° C. for 1 h. A solution of A33 (2.4 g, 5.96 mmol) in toluene (5 mL) at −70° C. was added. The mixture was stirred at −78° C. for 1 h. MeMgBr (5.93 mL, 17.8 mmol, 3 M in diethyl ether) was added at −78° C. The mixture was stirred at −78° C. for 1 h. The reaction mixture was quenched with saturated citric acid (100 mL). The mixture was extracted with EtOAc (3×100 mL), washed with brine (3×300 mL), dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel (PE / EtOAc=30 / 1 to 10 / 1) to give A34 (2 g) as a yellow solid. A34: 1 HNMR(400MHz, CDCl3) δ 3.67 (s, 3H), 2.36-2.18 (m, 2H), 2.01-1.92(m, 1H), 1.86-1.77(m, 1H), 1.72-1.61 (m, 3H),1.55-1.46 (m, 4H), 1.40-1.21 (m, 13H), 1.18-0.99(m, 7H), 0.95-0.86 (m, 5H), 0.81(s, 3H), 0.70-0.60 (m, 4H). LCMS Rt = 1.372 min (2 min chromatography, 30-90AB), C 27 H 47 O2[M+H] + MS ESI calculated value 418.3, [M+H-HO] + The actual measured value was 401. Step 4. To a solution of A34 (300 mg, 0.716 mmol) and Ti(i-PrO)4 (203 mg, 0.716 mmol) in THF (10 ml) was added EtMgBr (3 M in diethyl ether, 713 μL, 2.14 mmol). The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with saturated NH4Cl (5 mL). The mixture was filtered through a Celite pad. The filtrate was extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc = 20 / 1 to 10 / 1) to give This afforded compound 22 (77 mg, 26%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 2.00-1.92 (m, 1H),1.84-1.61 (m, 6H),1.53-0.83 (m,30H),0.80 (s, 3H), 0.76-0.71 (m, 2H), 0.69-0.60 (m,4H),0.47-0.40 (m, 2H). LCMS Rt=1. 317 min (2 min chromatography, 30-90AB), C 28 H 49 O2[M+H] + MS ESI calcd for 417, C 28 H 47 O[M+H-H2O] + The actual measured value was 399.

[0232] Example 11. Synthesis of Compounds 23 and 24 [ka] Step 1. To a solution of compound 6 (50 mg, 0.124 mmol) in MeOH (10 mL) was added Pd / C (10% wt, 26.6 mg, 24.8 mmol). After degassing with H2 three times, the reaction mixture was stirred under H2 (55 Psi) at 50 °C for 72 h. The reaction was filtered and the filtrate was concentrated to give the crude product, which was purified by silica gel column (PE / EtOAc = 15 / 1) to give compound 23 (10 mg, 20%) as a white solid and compound 24 (10 mg, 20%) as a white solid. Compound 23: 1 HNMR(400MHz, CDCl3) δ 3.81-3.75 (m, 1H),1.96-0.90 (m, 38H), 0.92(s,3H), 0.90(d, J = 6 .4 Hz, 3H), 0.64 (s, 3H). LCMS Rt=1.293 min (2.0 min chromatography, 30-90AB), C 27 H 49 O2[M+H] + MS ESI calculated value: 405, C 27 H 45 [M-2H2O+H] + The actual measured value was 369. Compound 24: 1 HNMR(400 MHz, CDCl3) δ 3.80-3.75 (m, 1H),2.00-1.90(m, 1H),1.90- 1.75 (m, 1H), 1.75-0.70 (m, 38H), 0.80 (s,3H), 0.70-0.60 (m, 4H).LCMS Rt = 1.282 min (2.0 min chromatography, 30-90AB), C 27 H 49 O2[M+H] + MS ESI calculated value: 405, C 27 H 45 [M-2H2O+H] + The actual measured value was 369.

[0233] Example 12. Synthesis of Compounds 25 and 26 [ka] Step 1. To a solution of t-BuOK (838 mg, 7.47 mmol) in THF (10 mL) was added Ph3PMeBr (2.66 g, 7.47 mmol) at 60° C. The mixture was stirred at 60° C. for 1 h. A13 (1 g, 2.49 mmol) was added at 60° C. The mixture was stirred at 60° C. for 2 h. The reaction was poured into water (30 mL) at 0° C. The mixture was extracted with EtOAc (2×20 mL), washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give A36 (0.9 g, 90%) as an off-white solid. 1 HNMR (400 MHz, CDCl3) δ5.33-5.28 (m, 1H),4.70-4.65 (m, 2H),2.45-2.40 (m, 1H),2.06-1.91 (m, 5H),1.89-1.74 (m, 2H),1. 74-1.67 (m, 4H), 1.56-1.20 (m, 11H),1.19-1.06 (m, 6H), 1.06-0.99 (m, 5H),0.99-0 .78 (m, 6H), 0.68 (s, 3H). Step 2. To a solution of A36 (800 mg, 2 mmol) in THF (5 mL) was added 9-BBN (40 mL, 20.0 mmol) at 0° C. The mixture was stirred at 25° C. for 1 h. NaOH (13.3 mL, 40 mmol, 3 M) and H2O2 (1.2 mL, 40 mmol) were added at 0° C. The mixture was stirred at 25° C. for 2 h. The reaction was poured into water. The mixture was extracted with EtOAc (2×50 mL). The combined organic layers were washed with saturated Na2S2O3 (2×50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to give A37 (400 mg) as an off-white solid. 1 HNMR(400MHz, CDCl3) δ 5.35-5.27 (m, 1H),4.00-3.90 (m, 1H), 3.90-3 .80 (m, 1H), 2.45-2.40 (m, 1H), 2.04-1.91(m, 3H),1.88-1.66 (m, 5H), 1.53-1.21 ( m, 10H), 1.20-0.87 (m, 23H), 0.68 (s, 3H). Step 3. To a solution of A37 (500 mg, 1.19 mmol) in DCM (10 mL) was added TEA (240 mg, 2.38 mmol) and Ac2O (181 mg, 1.78 mmol) at 25 °C. The reaction was stirred at 25 °C for 2 h. The reaction was quenched with saturated NaHCO3 (10 mL). The mixture was extracted with DCM (2 x 10 mL), washed with brine (2 x 10 mL), dried over Na2SO4, and concentrated to give A38 (450 mg, 82%) as an off-white solid. 1 HNMR(400 MHz, CDCl3) δ 5.35-5.25 (m, 1H),3.56-3.38 (m,2H) , 2.45-2.40 (m, 1H), 2.07-1.91 (m, 3H),1.89-1.67 (m, 3H),1.65-1.53 ​​(m, 5H), 1.4 9-1.32 (m, 8H), 1.32-1.09 (m, 10H),1.09-0.97 (m, 7H),0.97-0.87 (m, 7H), 0.68 (s , 3H). Step 4. A38 (450 mg) was purified by SFC (column: Chiralpak AD 250×30 mm ID, 5 μm; mobile phase: supercritical CO2 / MeOH+NH3H2O=60 / 40; flow rate: 60 ml / min; wavelength: 220 nm) to give A39 (200 mg) and A40 (150 mg) as off-white solids. Step 5. To a solution of A39 (200 mg, 0.435 mmol) in MeOH (10 mL) was added AcCl (17.0 mg, 0.217 mmol) at 25° C. The mixture was stirred at 25° C. for 2 h. The reaction was poured into water (10 mL) and extracted with THF (2×20 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4, and concentrated to give compound 25 (100 mg, 55%) as an off-white solid. 1 HNMR (400 MHz, CDCl3) δ 5.33-5.28(m, 1H), 3.57-3.36 (m, 2H), 2.46-2.38(m,1H),2.05-1.92 (m, 3H), 1.87-1.57 (m, 6H),1.52-1.34 (m, 7H), 1.28-1.20(m,3H),1.18-0.8 9 (m, 22H), 0.68 (s, 3H). LCMS Rt=1.328 min (2 min chromatography, 30-90AB_E), C 28 H 49 O2[M+H] + MS ESI calcd for 417, C 28 H 47 O[M+H-H2O] + The actual measured value was 399. Step 6. To a solution of A40 (150 mg, 0.326 mmol) in MeOH (10 mL) was added AcCl (12.7 mg, 0.163 mmol) at 25° C. The mixture was stirred at 25° C. for 2 h. The reaction was poured into water (10 mL) and extracted with THF (2×20 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4, and concentrated to give the crude product, which was purified by column chromatography on silica gel (PE / EtOAc=20 / 1 to 8 / 1) to give compound 26 (90 mg, 66%) as an off-white solid. 1 HNMR(400 MHz, CDCl3) δ 5.33-5.28 (m, 1H), 3.55-3.38 (m, 2H), 2.46-2.38 (m, 1H),2.05-1.93(m,3H), 1.87-1.58 (m, 5H), 1.51-0.89 (m, 3 3H), 0.68 (s, 3H). LCMS Rt=1.320 min (2 min chromatography, 3 0-90AB_E), C 28 H 49 O2[M+H] + MS ESI calcd for 417, C 28 H 47 O[M+H-H2O] + The actual measured value was 399.

[0234] Example 13. Synthesis of Compound 33 [ka] Step 1. To a solution of BHT (32.6 g, 148 mmol) in toluene (100 mL) was added dropwise trimethylaluminum (37.2 mL, 2 M in toluene, 74.4 mmol) at 0° C. The reaction mixture was stirred at 15° C. for 1.5 h. A33 (10 g, 24.8 mL) in toluene (100 mL) was added dropwise at −70° C. The resulting mixture was stirred at −70° C. for 1 h. EtMgBr (28.4 mL, 3.0 M in diethyl ether, 74.4 mmol) was added dropwise at −70° C. The reaction mixture was stirred at −70° C. for another 1 h. The reaction mixture was poured into saturated aqueous citric acid (2 L). The aqueous phase was extracted with EtOAc (3×1.5 L). The combined organic phase was washed with brine (2 L), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography eluting with PE:EtOAc=10:1 to give A41 (8 g, 75%) as a yellow solid. 1 HNMR(400 MHz, CDCl3) δ 3.66 (s, 3H), 2.30-2.15(m, 2H), 2.00-1.90 (m,1H),1.85-1.60(m, 5H), 1.50-1.15 (m, 15H), 1.14-0. 80(m, 18H), 0.69-0.55 (m, 4H). LCMS Rt=1.376 min (2.0 min chroma tography, 30-90AB), 100% purity, C 28 H 47 O2[M+H-H2O] + MS ESI calculated value 415, measured value 415. Step 2. To a solution of A41 (2 g, 4.62 mmol) in THF (50 mL) at 0° C. under N2, LiAlH4 (263 mg, 6.93 mmol) was added in small portions. The reaction was stirred at 0° C. for 30 min. The reaction was quenched with 1 M HCl (30 mL) at 0° C. and extracted with EtOAc (3×30 mL). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to give crude compound 33 (1.3 g, 70%) as an off-white solid. 100 mg of crude compound 33 was recrystallized from MeCN / DCM (10 mL / 10 mL) to give compound 33 (30 mg) as an off-white solid. 1 HNMR(400MHz, CDCl3) δ 3.68-3.60 (m, 2H),2.00-1.91 (m, 1H), 1.86 -1.74 (m, 1H), 1.70-1.58 (m, 4H), 1.56-1.44(m, 6H),1.42-1.31 (m, 6H), 1.30-1.18 (m, 7H), 1.14-0.95 (m, 7H), 0.93-0.81 (m,9H),0.93-0.79 (m, 1H), 0.68-0.58(m,4H). LCMS Rt=1.279 min (2.0 min chromatography, 30-90A B), C 27 H 47 O[M+H-H2O] + MS ESI calculated value 387, found value 387.

[0235] Example 14. Synthesis of Compounds 34, 35, and 36 [ka] Step 1. To a solution of A30 (2 g, 4.64 mmol) in THF (30 mL) was added LiAlH4 (260 mg, 6.85 mmol) at 0 °C. The mixture was stirred at 20 °C for 10 min. Water / THF (20 mL, 1 / 1) was added. The mixture was extracted with EtOAc (2 x 30 mL), washed with brine (2 x 100 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product A42 (1.7 g) as an off-white solid, which was used in the next step without further purification. 1 HNMR(400MHz, CDCl3) δ 5.35-5.25 (m, 1H), 3.70-3.60 (m, 2H),2.40-2.30 (m, 1H),2.05-1.60 (m,7H),1.60-1.35 (m, 10H), 1.25-1.15 (m, 5H),1.10-0.80 (m, 17H),0.67 (s, 3H). Step 2. To a solution of A42 (1.7 g, 4.22 mmol) in DCM (150 mL) was added DMP (3.2 g, 7.6 mmol) at 30° C. The mixture was stirred at 30° C. for 30 min. Water (100 mL) was added followed by NaHCO3 (4 g, solid). The organic phase was separated, washed with saturated Na2S2O3 (2×200 mL), brine (2×200 mL), dried over Na2SO4, filtered and concentrated in vacuo to give crude product A43 (2.1 g) as a yellow solid. 1 H NMR(400 MHz, CDCl3) δ 9.77 (s, 1H), 5.35-5.25 (m,1H),2.45-2.30 (m,3H), 2 .05-1.90(m, 4H), 1.85-0.90 (m, 28H), 0.85-0.75 (m, 4H), 0.68(s, 3H). Step 3. To a solution of A43 (1 g, crude) in THF (20 mL) was added methylmagnesium bromide (2.5 mL, 7.5 mmol, 3 M in ether) 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 34 (520 mg, impure) as an off-white solid. Compound 34 (520 mg, impure) was triturated with CH3CN (50 mL) at 80° C. to give 27 mg of pure compound 34 as an off-white solid, and 400 mg of impure compound 34 was used for SFC. 1 H NMR(400 MHz, CDCl3) δ 5.35-5.25 (m, 1H), 3.85-3.75(m,1H), 2.40-2.30(m, 1 H),2.05-1.90 (m, 3H), 1.85-1.55 (m, 6H),1.55-1.30 (m, 10H), 1.25-0.90 (m, 20H), 0.85-0.75 (m, 3H), 0.67 (s, 3H).LCMS R t = 1.295 minutes (2 minutes of chromatography Graphy, 30-90AB_E), C 28 H 47 O[M-H2O+H] + MS ESI calculated value 399, found value 399. Step 3. Compound 35 (400 mg, impure) was purified by SFC (column: AD (250 mm) * 30 mm, 5 um); Conditions: 0.1% NH3H2O ​​MeOH, 40% B; Flow rate (ml / min): 60) to give compound 35 (79 mg) and compound 36 (59 mg) as off-white solids. Compound 35: 1HNMR (400 MHz, CDCl3) δ 5.30-5.25 (m,1H),3.85-3.75 (m, 1H), 2.4 0-2.30 (m, 1H), 2.10-1.95 (m, 3H), 1.90-1.60(m, 4H), 1.45-1.28 (m, 11H), 1.25-0. 90 (m, 17H),0.88-0.82 (m, 4H), 0.78 (t, J= 7.2 Hz, 3H), 0.67 (s, 3H). LCMS R t =1.295 min (2 min chromatography, 30-90AB_E), [M-HO+H] + MS ESI calculated value 399, found value 399. Compound 36: 1 HNMR (400 MHz, CDCl3) δ 5.30-5.25 (m,1H),3.85-3.75 (m, 1H), 2.4 0-2.30 (m, 1H), 2.10-1.95 (m, 3H), 1.90-1.60(m, 4H), 1.50-1.17 (m, 11H), 1.14-0. 90 (m, 17H),0.88-0.82 (m, 4H), 0.78 (t, J= 7.2 Hz, 3H), 0.67 (s, 3H). LCMS R t = 1.295 min (2 min chromatography, 30-90AB_E), C 28 H 47 O[M-H2O+H] + MS ESI calculated value 399, found value 399.

[0236] Example 16. Synthesis of Compounds 37, 37-A, and 37-B [ka] Step 1. To a solution of compound 33 (500 mg, 1.23 mmol) in DCM (20 mL) was added DMP (1.04 g, 2.46 mmol) at 20° C. The reaction mixture was stirred at 20° C. for 1.5 h. The reaction mixture was quenched with saturated NaHCO3 (10 mL) at 20° C. The mixture was filtered and separated. The aqueous phase was extracted with DCM (20 mL). The combined organic phase was washed with saturated Na2S2O3 (50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated to give A44 (500 mg, crude) as a yellow solid. 1 HNMR(400MHz, CDCl3) δ 9.76 (s, 1H), 2.44-2.34(m, 2H), 1.99-1.92 (m, 1H), 1.63-1.51 (m, 9H), 1.43-1.31 (m,6H), 1.30-1.18 (m,6H), 1.12-0.97(m,7H), 0.94-0.85 (m, 7H), 0.82 (s, 3H),0.66-0.62 (m, 4H). Step 2. To a solution of A44 (500 mg, 1.24 mmol) in THF (20 mL) under N2 was added MeMgBr (2.06 mL, 3.0 M, 6.19 mmol) in one portion at 0 °C. After stirring at 20 °C for 30 min, the mixture was quenched with 50 mL of saturated NH4Cl and extracted with 50 mL of EtOAc. The separated organic phase was washed with 100 mL of brine, dried over Na2SO4, filtered and concentrated. The residue was purified by Combiflash (EtOAc in PE, 0% to 40%) to give compound 37 (350 mg, 67%) as an off-white solid. Delivered 27 mg. 1 HNMR(400MHz, CDCl3) δ 3.85-3.72 (m, 1H),1.99-1.91 (m, 1H),1.86-1.74 (m, 1H), 1.69-1.59 (m, 3H), 1.56 -1.50 (m, 3H),1.50-1.27 (m, 11H),1.26-1.16(m, 8H), 1.14-0.95 (m, 7H), 0.93-0.7 9 (m, 11H), 0.67-0.59 (m, 4H). LCMS Rt=1.297 min (2.0 min chromatography, 30-90AB), C 28 H 47 [M+H-2H2O] + MS ESI calculated value 383, measured value 383. Step 3. To a solution of compound 37 (300 mg, 0.716 mmol) in pyridine (10 mL) was added benzoyl chloride (501 mg, 3.57 mmol). The reaction was stirred at 20° C. for 2 h. The reaction was diluted with H2O (50 mL) and extracted with EtOAc (3×20 mL). The combined organic phase was washed with 1N HCl (100 mL), brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by Combiflash (0%-15% EtOAc in PE) to give A45 (270 mg, 72%) as a clear oil. 1 HNMR(400 MHz, CDCl3) δ 8.10-8.00 (m, 2H), 7.60-7.50 (m, 1H),7.50-7.40(m,2H),5.70-5.55 (m,1H), 2.00-1.90 (m, 1H), 1.85-1.15 (m , 23H), 1.10-0.75 (m, 20H),0.70-0.50 (m,4H). Step 4. A45 (270 mg, 0.516 mmol) was mixed with SFC (column: AD (250 mm * 30 mm, 5 um); Conditions: 0.1% NH3.H2O EtOH; Gradient 35% B; Gradient time (min): 30; Flow rate (ml / min): 60) to give A46 (Peak 1, 90 mg) as a white solid and A47 (Peak 2, 100 mg) as a white solid. A46: 1 H NMR (400 MHz, CDCl3)δ 8.10-8.00 (m, 2H),7.60-7.50(m, 1H), 7.50-7.40 ( m,2H),5.70-5.55 (m, 1H), 2.00-1.60 (m, 6H),1.55-1.25 (m, 14H), 1.20-1.10 (m, 7H ),1.10-0.75 (m, 17H), 0.70-0.50 (m, 4H). A47: 1 HNMR (400 MHz,CDCl3)δ 8.10-8.00 (m, 2H),7.60-7.50(m,1H), 7.50-7.40 (m,2 H), 5.70-5.55 (m, 1H), 2.00-1.60 (m, 7H),1.55-1.20 (m,20H), 1.20-0.80 (m, 17H), 0.70-0.50 (m, 4H). Step 5. To a solution of A46 (90 mg, 0.17 mmol) in THF (5 mL) was added a solution of MeOH (2 mL) and LiOH.H2O (72 mg, 1.72 mmol) at 25 °C. The mixture was stirred at 25 °C for 17 h. Water (5 mL) was added. The mixture was extracted with EtOAc (2 × 8 mL), washed with brine (2 × 10 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by flash column (0-30% EtOAc in PE, 50 min) to give compound 37-A (28 mg, 39%) as a white solid. 1 HNMR(400 MHz, CDCl3) δ 3.90-3.70 (m, HPLC R t = 6.82 min (8 min chromatography, 3 0-90_AB_1.2ml_E), C 28 H 47 [M+H-2H2O]+ MS ESI calculated value 383, actual value 383. Step 6. To a solution of A47 (100 mg, 0.19 mmol) in THF (5 mL) was added a solution of MeOH (2 mL) and LiOH.H2O (80 mg, 1.91 mmol) at 25 °C. The mixture was stirred at 25 °C for 17 h. Water (5 mL) was added. The mixture was extracted with EtOAc (2 × 8 mL), washed with brine (2 × 10 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by flash column (0-30% EtOAc in PE, 50 min) to give compound 37-B (57 mg, 71%) as a white solid. 1 HNMR(400 MHz, CDCl3) δ 3.90-3.70 (m, 1H), 2.00-1.60 (m, 7H),1.55-1.30(m,11H),1.25-1.15 (m, 9H), 1.10-0.75 (m, 1 8H), 0.70-0.50 (m, 4H). HPLC R t = 6.78 min (8 min chromatography, 30-90_AB_1.2ml_E), C 28 H 47 MS ESI calculated for [M+H-2H2O]+ 383, found 383.

[0237] Example 17. Synthesis of Compounds 38, 39, and 40 [ka] Step 1. To a solution of A43 (1 g, crude) and CsF (200 mg, 1.31 mmol) in THF (15 mL) was added TMSCF3 (1.76 g, 12.4 mmol) under nitrogen at 0 °C. The mixture was stirred at 20 °C for 1 h. TBAF (15 mL, 1 M in THF) was added. The mixture was stirred at 20 °C for an additional 16 h. The mixture was concentrated in vacuum to a mixture of 10 mL and DCM (30 mL) was added. The mixture was washed with water (3 × 50 mL), brine (2 × 50 mL), dried over Na2SO4, filtered and concentrated in vacuum to give the crude product, which was purified by flash column (0-25% EtOAc in PE, 80 min) to give compound 38 (400 mg, crude) as an off-white solid. Compound 38 (400 mg, crude) was triturated with CH3CN (30 mL) at 80 °C to give compound 38 (310 mg) as an off-white solid. 1 H NMR(400 MHz, CDCl3) δ 5.32-5.25 (m, 1H), 3.95-3.85(m,1H), 2.40-2.30(m, 1 H),2.10-1.60 (m, 10H), 1.55-1.30 (m, 9H),1.25-0.90 (m, 17H), 0.85 (t, J =7.6 Hz , 3H), 0.67 (s, 3H).LCMS R t = 1.308 min (2 min chromatography, 30-90AB_E), C 28 H 44 F3O[M-H2O+H] + MS ESI calculated value 453, measured value 453. Step 2. Compound 38 (300 mg) was purified by SFC (column: AD (250 mm) * Conditions: 0.1% NH3H2O ​​IPA, 35% B; Flow rate (ml / min): 60;) to give compound 39 (68 mg, 23%) and compound 40 (39 mg, 13%) as off-white solids. Compound 39: 1 HNMR (400 MHz, CDCl3) δ 5.32-5.25 (m,1H),3.95-3.85 (m, 1H), 2.4 0-2.30 (m, 1H),2.10-1.60 (m, 10H),1.55-1.30 (m, 10H), 1.25-0.90 (m, 16H), 0.85 (t, J =7.6 Hz, 3H), 0.68 (s, 3H). LCMS R t = 1.307 min (2 min chromatography, 30-90AB_E), C 28 H 44 F3O[M-H2O+H] + MS ESI calculated value 453, measured value 453. Compound 40: 1 HNMR (400 MHz, CDCl3) δ 5.32-5.25 (m,1H),3.95-3.85 (m, 1H), 2.4 0-2.30 (m, 1H),2.10-1.60 (m, 10H),1.55-1.25 (m, 13H), 1.20-0.90 (m, 13H), 0.85 (t, J =7.2 Hz, 3H), 0.68 (s, 3H). LCMS R t = 1.302 min (2 min chromatography, 30-90AB_E), C 28 H 44 F3O[M-H2O+H] + MS ESI calculated value 453, measured value 453.

[0238] Example 18. Synthesis of Compound 41 [ka] A30 (100 mg, 0.232 mmol) in THF (10 mL) under N To a suspension of Ti(i-PrO)4 (65.9 mg, 0.232 mmol) at 20 °C was added EtMgBr (0.27 mL, 0.812 mmol) dropwise. After stirring at 20 °C for 1 h, the mixture was quenched with 0.4 mL of saturated NH4Cl. The mixture was filtered. The filtrate was concentrated. The residue was purified by Combiflash (EtOAc in PE, 0% to 30%) to give compound 41 (42 mg, 42%) as an off-white solid. 1 HNMR(400 MHz, CDCl3) δ5.33-5.23 (m, 1H),2.41-2.31 (m, 1H), 2.07-1 .91 (m, 3H), 1.88-1.67 (m, 3H), 1.66-1.57(m, 3H),1.53-1.35 (m, 11H), 1.33-1.00 (m, 11H), 0.99-0.81 (m, 8H), 0.76-0.71 (m,2H),0.67 (s, 3H), 0.47-0.41 (m, 2H). LCMS Rt=1.309 min (2.0 min chromatography, 30-90AB), C 29 H 47 O[M+H-H2O] + MS ESI calculated value 411, measured value 411.

[0239] Example 19. Synthesis of Compound 42 [ka] To a suspension of A41 (150 mg, 0.346 mmol) and Ti(i-PrO)4 (98.3 mg, 0.346 mmol) in THF (10 mL) under N2 was added EtMgBr (0.4 mL, 1.21 mmol) dropwise at 20 °C. After stirring at 20 °C for 1 h, the mixture was quenched with 0.4 mL of saturated NH4Cl. The mixture was filtered. The filtrate was concentrated. The residue was purified by Combiflash (EtOAc in PE, 0% to 30%) to give compound 42 (78 mg, 52%) as an off-white solid. 1HNMR(400MHz, CDCl3) δ 2.00-1.92 (m, 1H),1.86-1.71 (m, 2H),1.69-1.56 (m, 6H), 1.53-1.33 (m, 10H), 1.29-1.16 (m,5H),1.14-0.96 (m, 7H), 0.94-0.81 (m, 11H), 0.75-0.71 (m, 2H), 0.67-0.60 (m,4H),0.46-0.42 (m, 2H). LCMS Rt=1 .343 min (2.0 min chromatography, 30-90AB), C 29 H 47 [M+H-2H2O] + MS ESI calculated value 395, found value 395.

[0240] Example 20. Synthesis of Compounds 43, 43-A, and 43-B [ka] Step 1. To a suspension of A44 (800 mg, 1.98 mmol) and CsF (150 mg, 0.99 mmol) in THF (20 mL) under N2 was added TMSCF3 (843 mg, 5.93 mmol) in one portion at 0 °C. After stirring at 20 °C for 1 h, TBAF (9.89 mL, 9.89 mmol, 1 M in THF) was added. The mixture was stirred at 20 °C for another 16 h. The mixture was quenched with 50 mL of saturated NH4Cl and extracted with 50 mL of EtOAc. The separated organic phase was washed twice with 100 mL of brine, dried over Na2SO4, filtered and concentrated. The residue was purified by Combiflash (EtOAc in PE, 0% to 40%) to give compound 43 (400 mg, 42%) as an off-white solid. 1 HNMR (400 MHz, CDCl3) δ3.98-3.85 (m, 1H),1.99-1.92 (m, 2H),1.87-1.74 (m, 1H), 1.69-1.56(m, 7H),1.53-1.31 (m, 10H),1.28-1.16 (m, 5H), 1.15-0.95 (m, 7H), 0.94-0.85 (m,7H), 0.82 (s, 3H),0.68-0.60 (m, 4H). LCMS Rt=1.351 min (2.0 min chromatography, 30-90AB), C 28 H 46 F3O[M+H-H2O] + MS ESI calculated value 455, measured value 455. Step 2. To a solution of compound 43 (350 mg, 0.740 mmol) in pyridine (10 mL) was added benzoyl chloride (416 mg, 2.96 mmol). The reaction was stirred at 50° C. for 48 h. The reaction was diluted with H2O (50 mL) and extracted with EtOAc (3×20 mL). The combined organic phase was washed with 1N HCl (100 mL), brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by Combiflash (0%-20% EtOAc in PE) to give A48 (200 mg, 47%) as a clear oil. 1 HNMR(400 MHz, CDCl3) δ 8.20-8.05 (m, 2H), 7.15-7.05 (m, 1H),7.50-7.40(m, 2H),5.60-5.50(m, 1H), 2.00-1.70 (m, 3H), 1.55-1.40 (m, 12H), 1.35-1.15 (m, 9H),1.10-0.90 (m,8H), 0.90-0.75 (m, 9H), 0.70-0.50 (m, 4H). Step 3. A48 (200 mg) was mixed with SFC (column: AD (250 mm * 30 mm, 5 um); Conditions: 0.1% NH3H2O ​​MeOH, 40% B; Flow rate (ml / min): 60) to give A49 (40 mg, 20%) as an oil and A50 (70 mg, 35%) as an off-white solid. Step 4. To a solution of A49 (40 mg) in THF (2 mL) was added MeOH (1 mL) and a solution of LiOH.HO (16.6 mg, 0.69 mmol) in HO (1 mL) at 25 °C. The mixture was stirred at 25 °C for 17 h. The mixture was extracted with EtOAc (2 × 5 mL), washed with brine (2 × 10 mL), dried over NaSO, filtered, and purified by flash column (0-30% EtOAc in PE) to give 43-A (20 mg, impure) as an off-white solid, which was triturated with CHCN (2 mL) at 25 °C, and then the filter cake was dissolved in CHCN (20 mL) at 80 °C. The solution was concentrated in vacuo to give 43-A (6 mg, 31%) as an off-white solid. 1 HNMR(400MHz, CDCl3) δ 4.00-3.85 (m, 1H), 2.10-1.75 (m, 3H), 1.70- 1.60 (m, 5H),1.55-1.20 (m, 16H), 1.15-0.75(m, 18H), 0.70-0.55 (m,4H). LCMS R t = 1.319 min (2 min chromatography, 30-90AB_E), C 28 H 46 F3O[M+H-H2O] + MS ESI calculated value 455, measured value 455. Step 5. To a solution of A50 (70 mg) in THF (3 mL) was added MeOH (2 mL) and a solution of LiOH.HO (50.7 mg, 1.2 mmol) in HO (2 mL) at 25 °C. The mixture was stirred at 25 °C for 17 h. The mixture was extracted with EA (2 × 6 mL), washed with brine (2 × 10 mL), dried over NaSO, filtered and purified by flash column (0-30% EtOAc in PE, 1 h) to give 43-B (40 mg, impure) as an oil, which was recrystallized from 4 mL of CHCN at 80 °C to give 43-B (23 mg, 58%) as an off-white solid. 1HNMR(400 MHz, CDCl3) δ 4.00-3.85 (m,1H), 2.10-1.75 (m, 3H),1.70-1.60 (m,5H),1.55- 1.20 (m, 16H), 1.15-0.75 (m, 18H),0.70-0.55 (m,4H).LCMS R t =1.315 min (2 min chromatography, 30-90AB_E), C 28 H 46 F3O[M+H-H2O] + MS ESI calculated value 455, measured value 455. material and method

[0241] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it is understood that other process conditions can also be used unless otherwise stated. Optimal reaction conditions may vary with the specific reactants or solvents used, but such conditions can be determined by those skilled in the art by routine optimization.

[0242] 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.

[0243] 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 following schemes are detailed for the preparation of the representative neurostimulant steroids listed herein. 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.

[0244] As reported herein 1 It will be understood that the H-NMR (e.g., for a δ (ppm) region of about 0.5 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.

[0245] 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

[0246] 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)) Using whole-cell patch clamp techniques, GrunN1 expressed in mammalian cells was The effects of the compounds on the glutamate receptor GluN2A were examined. 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] In Table 1, "A" indicates 10-100%, "B" indicates >100% enhancement; "ND" indicates not measurable or not determined. Other embodiments

[0247] 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.

[0248] Moreover, the 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, when the invention or aspects of the invention are referred to as comprising certain elements and / or features, it is to be understood that certain embodiments of the invention or aspects of the invention consist of or consist essentially of such elements and / or features. For purposes of simplicity, those embodiments may not be expressly set forth herein in these exact terms. 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 the understanding of one of ordinary skill in the art, values ​​expressed as ranges can assume any particular value or subrange within the range set forth in various embodiments of the invention to the tenth of the unit of the lower limit of that range, unless the context clearly dictates otherwise.

[0249] 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.

[0250] 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.

[0251] In an embodiment of the present invention, for example, the following items are provided: (Item 1) Formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is C 1~6 is alkyl; R 2 and R 3 Each of the groups is independently hydrogen, halogen, C 1~6 is alkyl or carbocyclyl; or R 2 and R 3 together with the carbon atoms to which they are attached form a 3- to 8-membered ring; R 6 is absent or is hydrogen; R 7 and R 8 Each of the groups is independently hydrogen, halogen, C 1~6 is alkyl or carbocyclyl; or R 7 and R 8 each together with the carbon atom to which they are attached form a 3- to 8-membered ring; or R 2 and R 7 together with the carbon atoms to which they are attached form a 3- to 8-membered ring; n is 1, 2 or 3; [ka] represents a single or double bond, where [ka] When is a double bond, the other [ka] is a single bond; [ka] When one of the groups is a double bond, R 6 does not exist, A compound or a pharma- ceutically acceptable salt thereof. (Item 2) each [ka] is a single bond. (Item 3) R 1 is methyl (e.g., -CHF2, -CF3, -CH2OCH3 or -CH2OCH2CH3), ethyl or isopropyl. (Item 4) R 1 is methyl or ethyl. (Item 5) R 2 and R 3 each independently represents hydrogen, C 1~6 alkyl or carbocyclyl, or R 2 and R 3 The compound according to item 1, wherein, together with the carbon atom to which they are attached, form a 3- to 8-membered ring. (Item 6) 6. The compound according to item 5, wherein the 3- to 8-membered ring is a carbocyclyl ring (eg, cyclopropyl). (Item 7) R 2 and R 3 each independently represents hydrogen, C 1~6 6. The compound according to item 5, wherein the aryl group is alkyl or carbocyclyl. (Item 8) R 2 and R 3each is independently hydrogen, methyl (e.g., -CH3, -CF3), ethyl (e.g., -CH2CH3, -CH2CF3), propyl, isopropyl, cyclopropyl, or butyl. (Item 9) R 2 is hydrogen, methyl (e.g., -CH3, -CF3) or ethyl; The compounds listed above. (Item 10) R 3 is methyl (e.g., -CH3, -CF3), ethyl (e.g., -CH2CH3, CH2CF3), propyl, isopropyl, cyclopropyl or butyl. (Item 11) R 2 is hydrogen and R 3 But, C 1~6 8. The compound according to item 7, wherein the aryl group is alkyl. (Item 12) R 2 But, C 1~6 is alkyl, R 3 But, C 1~6 8. The compound according to item 7, wherein the aryl group is alkyl. (Item 13) [ka] Each of is a single bond. (Item 14) R 7 and R 8 is hydrogen. (Item 15) The compound according to item 1, wherein n is 1. (Item 16) n is 1, and R 7 and R 8 is hydrogen. (Item 17) The compound of formula (I) may be represented by formula (II): [ka] or a pharma- ceutically acceptable salt thereof. (Item 18) The compound of formula (I) is represented by formula (II-A) or formula (II-B): [ka] 18. The compound according to item 17, which is a compound of formula (I) or a pharma- ceutically acceptable salt thereof. (Item 19) The compound of formula (I) has formula (II-Bi) or formula (II-B-ii): [ka] 18. The compound according to item 17, which is a compound of formula (I) or a pharma- ceutically acceptable salt thereof. (Item 20) The compound of formula (I) has the formula (II-B-iii): [ka] 18. The compound according to item 17, which is a compound of formula (I) or a pharma- ceutically acceptable salt thereof. (Item 21) The compound of formula (I) may be represented by formula (III): [ka] or a pharma- ceutically acceptable salt thereof. (Item 22) The compound of formula (III) is represented by formula (III-A) or formula (III-B): [ka] 22. The compound according to claim 21, which is a compound of formula (I) or a pharma- ceutically acceptable salt thereof. (Item 23) The compound of formula (III-B) is represented by formula (III-C) or formula (III-D): [ka] 22. The compound according to claim 21, which is a compound of formula (I) or a pharma- ceutically acceptable salt thereof. (Item 24) The compound of formula (III-A) may be represented by formula (III-E) or formula (III-F): [ka] 22. The compound according to claim 21, which is a compound of formula (I) or a pharma- ceutically acceptable salt thereof. (Item 25) The compound of formula (III) has the formula (III-Aia) or the formula (III-Bia): [ka] 22. The compound according to claim 21, which is a compound of formula (I) or a pharma- ceutically acceptable salt thereof. (Item 26) R 1 is methyl (e.g., -CHF2, -CF3, -CH2OCH3 or -CH2OCH2CH3), ethyl or isopropyl. (Item 27) R 2 and R 3 each independently represents hydrogen, C 1~6 alkyl or carbocyclyl, or R 2 and R 3 together with the carbon atom to which they are attached form a 3- to 8-membered ring. (Item 28) R 2 and R 3each independently represents hydrogen, C 1~6 28. The compound according to item 27, which is alkyl or carbocyclyl. (Item 29) R 2 and R 3 each independently represents hydrogen, methyl (e.g., -CH3, -CF3), ethylene 29. The compound according to item 28, wherein the aryl is ethyl (e.g., -CH2CH3, -CH2CF3), propyl, isopropyl, cyclopropyl or butyl. (Item 30) R 2 30. The compound according to item 29, wherein is hydrogen, methyl (e.g., -CH3, -CF3) or ethyl. (Item 31) R 3 is methyl (e.g., -CH3, -CF3), ethyl (e.g., -CH2CH3, -CH2CF3), propyl, isopropyl, cyclopropyl or butyl. (Item 32) The compound is [ka] or a pharma- ceutically acceptable salt thereof, selected from the group consisting of the compound according to item 21. The compound of formula (I) may be represented by formula (IV): [ka] or a pharma- ceutically acceptable salt thereof. (Item 34) R 1 is methyl (e.g., -CHF2, -CF3, -CH2OCH3 or -CH2OCH2CH3), ethyl or isopropyl. (Item 35) R 2 and R 3 each independently represents hydrogen, C 1~6alkyl or carbocyclyl, or R 2 and R 3 and R 1 and R 2 are, taken together with the carbon atom to which they are attached, to form a 3- to 8-membered ring. (Item 36) R 2 and R 3 each independently represents hydrogen, C 1~6 36. The compound according to item 35, which is alkyl or carbocyclyl. (Item 37) R 2 and R 3 37. The compound according to item 36, wherein each of is independently hydrogen, methyl (e.g., -CH3, -CF3), ethyl (e.g., -CH2CH3, CH2CF3), propyl, isopropyl, cyclopropyl, or butyl. (Item 38) R 2 is hydrogen, methyl (e.g., -CH3, -CF3) or ethyl; The compound described. (Item 39) R 3 is methyl (e.g., -CH3, -CF3), ethyl (e.g., -CH2CH3, -CH2CF3), propyl, isopropyl, cyclopropyl, butyl. (Item 40) The compound is [ka] 34. The compound according to item 33, wherein: (Item 41) The compound of formula (I) has the formula (V): [ka] or a pharma- ceutically acceptable salt thereof. (Item 42) The compound of formula (I) has the formula (VA): [ka] 18. The compound according to item 17, which is a compound of formula (I) or a pharma- ceutically acceptable salt thereof. (Item 43) The compound of formula (I) has the formula (VB): [ka] or a pharma- ceutically acceptable salt thereof. (Item 44) The compound of formula (III) is a compound of formula (VC) or formula (VD): [ka] 22. The compound according to claim 21, which is a compound of formula (I) or a pharma- ceutically acceptable salt thereof. (Item 45) The compound of formula (I) has the formula (VEi): [ka] or a pharma- ceutically acceptable salt thereof. (Item 46) The compound of formula (I) has the formula (VE-ii) or (VE-iii): [ka] or a pharma- ceutically acceptable salt thereof. (Item 47) The compound is [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof. (Item 48) A pharmaceutical composition comprising the compound according to item 1 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier. (Item 49) A method for inducing sedation or anesthesia, comprising administering to a subject an effective amount of a compound according to item 1 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof. (Item 50) A method for treating or preventing a disorder described herein, comprising administering to a subject in need of said treatment or prevention an effective amount of a compound described in item 1 or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition thereof. (Item 51) 51. The method according to item 50, wherein the disorder is a gastrointestinal (GI) disorder, 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, perianal abscesses, anal fistulas), colon polyps, cancer, colitis. (Item 52) 51. The method of item 50, wherein the disorder is inflammatory bowel disease. (Item 53) 51. The method of item 50, wherein the disorder is cancer, diabetes or a sterol synthesis disorder. (Item 54) 51. The method of item 50, wherein the disorder is a metabolic disorder. (Item 55) 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 according to item 1 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof. (Item 56) The CNS-related symptoms include adjustment disorder, anxiety disorder (obsessive-compulsive disorder, post-traumatic stress disorder, and 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 those with mutations in the Shank family of proteins (e.g., Shank3) , neurodevelopmental disorders (including Rett syndrome, tuberous sclerosis syndrome), multiple sclerosis, sterol synthesis disorders, pain (including acute and chronic pain), encephalopathy 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's disease), stroke, traumatic brain injury, movement disorders (including Huntington's disease and Parkinson's disease), visual disorders, hearing loss and tinnitus. (Item 57) 56. The method of claim 55, wherein the disorder is a sterol synthesis disorder.

Claims

[Claim 1] In vivo efficacy.

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