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 on 6 July 2015, and U.S. Provisional Application No. 62 / 280,394, filed on 19 January 2016, the contents of each of these U.S. Provisional Applications being incorporated herein by reference in their entirety. [Background technology]

[0002] Background of the Invention NMDA receptors are heteromeric complexes containing NR1, NR2, and / or NR3 subunits, possessing distinct recognition sites for exogenous and endogenous ligands. These recognition sites include binding sites for glycine as well as binding sites for glutamate agonists and regulators. 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 modulators may be useful as nootropics and as therapeutic agents with potential clinical applications in the treatment of mental 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 modulators may be useful as therapeutic agents with potential clinical applications in the treatment of mental disorders in which glutamatergic transmission is pathologically increased (e.g., treatment-resistant depression). Oxysterols, derived from cholesterol, have been shown to potently and selectively modulate the function of NMDA receptors. Novel and improved oxysterols that modulate NMDA receptors are needed to prevent and treat conditions associated with NMDA expression and function. The compounds, compositions, and methods described herein are directed toward this purpose. [Prior art documents] [Non-patent literature]

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

[0004] Summary of the Invention Substituted oxysterols useful for the prevention and / or treatment of a wide range of disorders, including but not limited to NMDA-mediated disorders, are provided herein. These compounds are expected to exhibit improved in vivo efficacy, pharmacokinetic (PK) properties, oral bioavailability, formulation suitability, stability, and / or safety compared to other oxysterols. Pharmaceutical compositions comprising the compounds of the present invention, as well as methods of use and treatment thereof, are further provided. In one phase, equation (I): [ka] Compounds described herein or pharmaceutically acceptable salts thereof are provided herein, where R 1 C 1~6 Alkyl; R 2 and R 3 Each of them independently contains hydrogen and C 1~6 Alkyl or carbocyric; or R 2 and R 3, together with the carbon atoms to which they are bonded, form a 3- to 8-membered ring; R 6 is absent or is hydrogen; R 7 and R 8 each are independently hydrogen, halogen, C 1~6 alkyl or carbocyclyl; or R 7 and R 8 each, together with the carbon atoms to which they are bonded, form a 3- to 8-membered ring; or R 2 and R 7 , together with the carbon atom to which they are bonded, form a 3- to 8-membered ring; n is 1, 2 or 3; Chemical Formula represents a single bond or a double bond, wherein when one of Chemical Formula is a double bond, the other Chemical Formula is a single bond; Chemical Formula , when one is a double bond, R 6 is absent.

[0005] In some embodiments, R 1 is substituted C 1~6 alkyl. In some embodiments, R 1 is unsubstituted C 1~6 alkyl. In some embodiments, R 1 is methyl (for example, -CHF2, -CH3, -CF3, -CH2OCH3 or -CH2OCH2CH3), ethyl or isopropyl. In some embodiments, R 1is -CH3. In some embodiments, R 1 It is ethyl.

[0006] In some embodiments, R 2 and R 3 Each of them independently contains hydrogen and C 1~6 It is alkyl or carbocyric, or R 2 and R 3 These, together with the carbon atoms to which they are bonded, form a 3- to 8-membered ring. In some embodiments, the 3- to 8-membered ring is a carbocykyl ring (e.g., cyclopropyl). In some embodiments, R 2 and R 3 Each of them independently contains hydrogen and C 1~6 It is alkyl or carbocyric. In some embodiments, R 2 and R 3 Each of these 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 substitution C 1~6 It is alkyl. Several implementations In terms of form, R 2 is unsubstituted C 1~6 It is alkyl.

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

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

[0010] In some embodiments, R 3These are 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 C 1~6 Alkyl (e.g., methyl (e.g., -CH3, -CF3), ethyl, isopropyl). In some embodiments, R 2 C 1~6 It is alkyl, R 3 C 1~6 It is alkyl. In some embodiments, R 2 and R 3 is -CH3. In some embodiments, R 2 It is -CH3, and R 3 is -CF3. In some embodiments, R 2 It is -CH3, and R 3 is ethyl. In some embodiments, R 2 It is -CH3, and R 3 It is isopropyl.

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

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

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

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

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

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

[0018] In some embodiments, the compound of formula (I) is of formula (II): [ka] It is a compound of or a pharmaceutically acceptable salt of the compound.

[0019] In some embodiments, the compound of formula (II) is either formula (II-A) or formula (II-B): [ka] It is a compound of or a pharmaceutically acceptable salt of the compound.

[0020] In some embodiments, the compound of formula (I) is formula (II-Bi) or formula (II-B-ii): [ka] It is a compound of or a pharmaceutically acceptable salt of the compound.

[0021] In some embodiments, the compound of formula (I) is of formula (II-B-iii): [ka] It is a compound of or a pharmaceutically acceptable salt of the compound.

[0022] In some embodiments, the compound of formula (I) is formula (III): [ka] It is a compound of or a pharmaceutically acceptable salt of the compound.

[0023] In some embodiments, the compound of formula (III) is either formula (III-A) or formula (III-B): [ka] It is a compound of or a pharmaceutically acceptable salt of the compound.

[0024] In some embodiments, the compound of formula (III-B) is either of formula (III-C) or formula (III-D): [ka] It is a compound of or a pharmaceutically acceptable salt of the compound.

[0025] In some embodiments, the compound of formula (III-A) is formula (III-E) or formula (III-F): [ka] It is a compound of or a pharmaceutically acceptable salt of the compound.

[0026] In some embodiments, the compound of formula (III) is formula (III-Aia) or formula (III-Bia): [ka] It is a compound of or a pharmaceutically acceptable salt of the compound.

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

[0028] In some embodiments, R 2 and R 3 Each of them independently contains hydrogen and C 1~6 It is alkyl or carbocyric, or R 2 and R 3 These atoms, together with the carbon atoms to which they are bonded, form a 3- to 8-membered ring.

[0029] In some embodiments, R 2 and R 3 Each of them independently contains hydrogen and C 1~6 It is alkyl or carbocyric.

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

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

[0032] In some embodiments, R 3 These are 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 pharmaceutically acceptable salt thereof.

[0034] In some embodiments, the compound of formula (I) is a compound of formula (IV):

Chemical Formula

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

[0036] In some embodiments, R 2 and R 3 are each independently 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.

[0037] In some embodiments, R 2 and R 3 are each independently hydrogen, C 1~6 alkyl or carbocyclyl.

[0038] In some embodiments, R 2 and R 3 are each independently hydrogen, methyl (for example, -CH3, -CF3), ethyl (for example, -CH2CH3, CH2CF3), propyl, isopropyl, cyclopropyl or butyl.

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

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

[0041] In some embodiments, the compound is

Chem.

[0042] In some embodiments, the compound of formula (I) is a compound of formula (V):

Chem.

[0043] In some embodiments, the compound of formula (I) is a compound of formula (V-A):

Chem.

[0044] In some embodiments, the compound of formula (I) is a compound of formula (V-B):

Chem.

[0045] In some embodiments, the compound of formula (III) is a compound of formula (V-C) or formula (V-D):

Chem.

[0046] In some embodiments, the compound of formula (I) is of formula (VE): [ka] It is a compound of or a pharmaceutically acceptable salt of the compound.

[0047] In some embodiments, the compound of formula (VE) is of formula (VEi): [ka] It is a compound of or a pharmaceutically acceptable salt of the compound.

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

[0049] [ka] The compound or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is [ka] [ka] [ka] [ka] or selected from pharmaceutically acceptable salts thereof.

[0050] In certain contexts, pharmaceutical compositions comprising compounds described herein or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers are provided herein.

[0051] In a certain context, a method for inducing sedation or anesthesia is provided herein, which comprises administering an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof, to a subject.

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

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

[0054] In some embodiments, the disorders are gastrointestinal (GI) disorders, e.g., constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) (e.g., ulcerative colitis, Crohn's disease), structural disorders affecting GI, anal disorders (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas), colon polyps, cancer, and colitis.

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

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

[0057] A method for treating or preventing CNS-related symptoms in a given context, comprising an effective amount of the compound described herein or A method is provided herein that comprises the step of administering a pharmaceutically acceptable salt or a pharmaceutically acceptable composition thereof. In some embodiments, CNS-related symptoms include adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, and social phobia), cognitive disorders (including Alzheimer's disease and other forms of dementia (e.g., frontotemporal dementia)), dissociative disorders, eating disorders, mood disorders (including depression (e.g., postpartum depression), bipolar disorder, dysthymic disorder, and suicidal ideation), schizophrenia or other psychotic disorders (including schizoaffective disorder), sleep disorders (including insomnia), substance-related disorders, personality disorders (including obsessive-compulsive personality disorder), and autism spectrum disorders (Shank group). These include mutations in the protein (e.g., Shank3), neurodevelopmental disorders (including Rett syndrome and tuberous sclerosis syndrome), multiple sclerosis, sterol synthesis disorders, pain (including acute and chronic pain; headaches, e.g., migraines), encephalopathy secondary to a certain condition (including hepatic encephalopathy and anti-NMDA receptor encephalitis), paroxysmal disorders (status epilepticus and monogenotypic epilepsy, e.g., Dravet disease), stroke, traumatic brain injury, motor 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 impairment is sterol synthesis impairment.

[0060] In some embodiments, the disorder is Smith-Lemle-Oppitz syndrome (SLOS). In some embodiments, the disorder is desmosterosis. In some embodiments, the disorder is sitosterolemia. In some embodiments, the disorder is cerebral tenosynovitis 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 purposes and advantages will become apparent to those skilled in the art by considering the following detailed description, examples, and claims. definition chemical definition

[0062] The definitions of specific functional groups and chemical terms are explained in detail below. Chemical elements are identified according to the periodic table (CAS version, Handbook of Chemistry and Physics, 75th edition, inside cover), and specific functional groups are generally defined as described therein. Furthermore, general rules of organic chemistry, as well as specific functional parts and reactivity, are described 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 This is described in York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0063] The compounds described herein may contain one or more chiral centers and therefore may exist in 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 in the form of mixtures of stereoisomers (including racemic mixtures and mixtures concentrated in one or more stereoisomers). The isomers may be isolated from the mixture 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 may 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 (edited by Eliel, Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention further includes the compounds described herein as individual isomers substantially free from other isomers, and / or as mixtures of various isomers.

[0064] The compounds described herein may also include one or more isotopic substitutions. For example, H is 1 H, 2 H (D or deuterium), and 3 It can be any isotopic form containing H (T or tritium); C is 12 C, 13 C, and 14 It can be any isotopic form containing C; O is 16 O and 18 It can be any isotopic form containing O; and so on.

[0065] When a range of values ​​is enumerated, it is intended to include each value and subrange within that range. For example, "C 1~6 "Alkyl" refers to 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 It is intended to include alkyl groups.

[0066] The following terms are intended to have the meanings presented below and are useful in understanding the intended scope of this specification and the invention. When describing the invention, which may include compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms have the meanings below unless otherwise indicated, where they exist. It should also be understood that, when described herein, any of the parts defined below may be substituted with various substituents, and that each definition is intended to include such substituted parts within the scope shown below. Unless otherwise stated, the term “substituted” should be defined as shown below. It should further be understood that, when used herein, the terms “group” and “radical” may be considered interchangeable. The articles “a” and “an” may be used herein to refer to one or more (i.e., at least one) grammatical objects of the article. For example, “an analogue” means one analog or more analogs.

[0067] "Aliphatic" refers to alkyl, alkenyl, alkynyl, or carbocykyl groups as defined herein.

[0068] "Alkyl" refers to a radical of a linear or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C"). 1~20 This refers to "alkyl". In some embodiments, A lukyl group has 1 to 12 carbon atoms ("C 1~12 ("alkyl"). In some embodiments, the alkyl group has 1 to 10 carbon atoms ("C"). 1~10 Alkyl). In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C"). 1~9 Alkyl). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C"). 1~8Alkyl). In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C"). 1~7 Alkyl). In some embodiments, the alkyl group has 1 to 6 carbon atoms (also referred to herein as "lower alkyl"). 1~6 Alkyl). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C"). 1~5 Alkyl). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C"). 1~4 (alkyl). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C"). 1~3 Alkyl). In some embodiments, the alkyl group has one to two carbon atoms ("C"). 1~2 Alkyl). In some embodiments, the alkyl group has one carbon atom ("C1 alkyl"). In some embodiments, the alkyl group has two to six carbon atoms ("C1 alkyl"). 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 others. Unless otherwise specified, each alkyl group may be independently substituted as needed, i.e., unsubstituted ("unsubstituted alkyl") or with one or more substituents; for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, the alkyl group is unsubstituted C 1~10 It is an alkyl group (e.g., -CH3). In certain embodiments, the alkyl group is a substituted C 1~10It is an alkyl group. Common abbreviations for alkyl groups 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 that has had two hydrogen atoms removed to provide a divalent radical, and this alkyl group may be substituted or unsubstituted. Examples of unsubstituted alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), and hexylene (-CH2CH2CH2CH2CH2CH2-). Exemplary substituted alkylene groups, for example, 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 include, but are not limited to, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, and -CH2CH2C(CH3)2-. When a range or number of carbon atoms is provided for a particular alkylene group, that range or number is understood to refer to the range or number of carbon atoms in a divalent carbon linear chain. The alkylene group may be substituted with one or more substituents as described herein, or it may be unsubstituted.

[0070] An "alkenyl" is a molecule containing 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 linear or branched hydrocarbon group having a double bond ("C") 2~20This refers to an alkenyl group. In certain embodiments, the alkenyl group does not contain any triple bond. In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C"). 2~10 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C"). 2~9 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C"). 2~8 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C"). 2~7 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C"). 2~6 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C"). 2~5 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C"). 2~4 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C"). 2~3 "Alkenyl"). In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). One or more carbon-carbon double bonds may be located internally (e.g., 2-butenyl) or at the 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), and butadienyl (C4). 2~6 An example of an alkenyl group is the aforementioned C 2~4Examples of alkenyl groups include pentenyl (C5), pentadienyl (C5), and hexenyl (C6). Further examples of alkenyls include heptenyl (C7), octenyl (C8), and octatrienyl (C8). Unless otherwise specified, each presence of an alkenyl group can be independently substituted as needed, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, the alkenyl group is an unsubstituted C 2~10 It is an alkenyl. In certain embodiments, the alkenyl group is a substituted C 2~10 It is Alkenil.

[0071] "Alkynnyl" refers to a radical of a linear or branched 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). 2~20 This refers to an "alkynyl" group. In certain embodiments, the alkynyl group contains no double bonds at all. In some embodiments, the alkynyl group has 2 to 10 carbon atoms ("C"). 2~10 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 9 carbon atoms ("C"). 2~9 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C"). 2~8 In some embodiments, the alkynyl group has 2 to 7 carbon atoms ("C"). 2~7 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C"). 2~6 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C"). 2~5 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C"). 2~4("Alkynyl"). In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C"). 2~3 "Alkynyl"). In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). One or more carbon-carbon triple bonds may be located internally (e.g., 2-butynyl) or at the terminal (e.g., 1-butynyl). 2~4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), and 2-butynyl (C4). 2~6 An example of an alkenyl group is the aforementioned C 2~4 Examples include alkynyl groups, as well as pentynyl (C5) and hexynyl (C6). Further examples of alkynyls include heptynyl (C7) and octinyl (C8). Unless otherwise specified... To the extent that, each alkynyl group may be independently substituted as needed, i.e., unsubstituted ("unsubstituted alkynyl") or with one or more substituents; for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkynyl"). In certain embodiments, the alkynyl group is an unsubstituted C 2~10 It is an alkynyl group. In certain embodiments, the alkynyl group is a substituted C 2~10 It is alkinyl.

[0072] The term “heteroalkyl” as used herein means an alkyl group as defined herein, further comprising one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) in the parent chain, wherein 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 carbon atoms and the parent molecule, i.e., between bonding points. In certain embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("hetero-C"). 1~10This refers to an alkyl group. In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3 or 4 heteroatoms (hetero C 1~9 A heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3 or 4 heteroatoms ("heteroC"). 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 A heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3 or 4 heteroatoms ("hetero C"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3 or 4 heteroatoms ("hetero C"). 1~7 A heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ("hetero C"). In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ("hetero C"). 1~6 A heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("hetero C"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("hetero C"). 1~5 A heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms ("hetero C 1~4 A heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom ("hetero C"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom ("hetero C"). 1~3 A heteroalkyl group is a saturated group having one to two carbon atoms and one heteroatom ("hetero C"). In some embodiments, a heteroalkyl group is a saturated group having one to two carbon atoms and one heteroatom ("hetero C"). 1~2 In some embodiments, a heteroalkyl group is a saturated group having one carbon atom and one heteroatom ("heteroC1 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms ("heteroC1 alkyl"). 2~6 The heteroalkyl group is an alkyl group. Unless otherwise specified, each case of a heteroalkyl group is independently either unsubstituted ("unsubstituted heteroalkyl group") or substituted with one or more substituents ("substituted heteroalkyl group"). In certain embodiments, the heteroalkyl group is an unsubstituted heteroalkyl group. 1~10It is alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC 1~10 It is alkyl.

[0073] "Aryl" refers to a radical ("C") of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) in which 6 to 14 ring carbon atoms and 0 heteroatoms are provided to the aromatic ring system. 6~14 This refers to an aryl group. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10 "Aryl"; for example, naphthyl (such as 1-naphthyl and 2-naphthyl). In some embodiments, the 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 with one or more carbocyrillic or heterocyclyl groups, where the bonding radical or bond site is located on the aryl ring, and in such cases the number of carbon atoms is Next, we will point out the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from acetantrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluorantene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indan, indene, naphthalene, octacene, octafen, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentafen, 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 presence of an aryl group is independently substituted as necessary, i.e., either unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, the aryl group is an unsubstituted C 6~14 It is aryl. In certain embodiments, the aryl group is substituted C 6~14 It is Ariel.

[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 groups.

[0075] Typical examples of substitution aryls include the following: [ka] Here, R 56 and R 57 One of them can be hydrogen, and R 56 and R 57At least one of them is independently a C1-C8 alkyl, C1-C8 haloalkyl, 4-10 member heterocyclyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, or NR. 58 COR 59 , NR 58 SOR 59 , NR 58 SO2R 59 COOalkyl, COOaryl, CONR 58 R 59 CONR 58 Ure 59 , NR 58 R 59 SO2NR 58 R 59 Selected from S-alkyl, SOalkyl, SO2alkyl, S-aryl, SOaryl, SO2aryl; or R 56 and R 57 These can be linked together to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms (including, as necessary, one or more heteroatoms selected from the group N, O, or S). 60 and R 61 These are independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, and C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl substitution C6~C 10 These are aryl, 5-10 member heteroaryl, or substituted 5-10 member heteroaryl.

[0076] A "condensed aryl" refers to an aryl ring in which two of its ring carbons are shared with a second aryl ring, heteroaryl ring, carbocykyl ring, or heterocyclyl ring.

[0077] "Aralkyl" refers to an optionally substituted alkyl group, which is a subset of alkyl and aryl groups as defined herein and is optionally substituted with an optionally substituted aryl group.

[0078] A "heteroaryl" is a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system in which a ring carbon atom and 1-4 ring heteroatoms are provided to the aromatic ring system (for example, in a cyclic arrangement) A heteroaryl group refers to a radical having 6 or 10 π electrons shared between them, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the bond site can be a carbon or nitrogen atom, where the valency allows. A heteroaryl bicyclic ring system may contain one or more heteroatoms on 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 bond site is located on the heteroaryl ring, and in such cases, the number of ring members still points 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 bond site is located on the aryl or heteroaryl ring, and in such cases, the number of ring members points to the number of ring members in the fused (aryl / heteroaryl) ring system. One ring is a bicyclic heteroaryl group that does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl), and the bond site can be located on either ring, i.e., on the ring containing a heteroatom (e.g., 2-indolyl) or on the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0079] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system in which a ring carbon atom and 1-4 ring heteroatoms are provided to 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 a ring carbon atom and 1-4 ring heteroatoms are provided to 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 a ring carbon atom and 1-4 ring heteroatoms are provided to 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, a 5-6 membered heteroaryl group has one or two ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl group has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each presence of a heteroaryl group is independently substituted as necessary, 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] Examples of five-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Examples of five-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Examples of five-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Examples of five-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Examples of six-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Examples of six-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Examples of six-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetradinyl, respectively. Examples of seven-membered heteroaryl groups containing one heteroatom include azepinyl and oxepinyl. Examples of 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranil, benzoisofuranil, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolidinyl, and prinyl. Examples of 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthylidinyl, pteridinyl, quinolinil, isoquinolinil, sinnolinil, quinoxalinil, phthalazinyl, and quinazolinil.

[0081] Typical examples of heteroaryls include: [ka] These are listed, where each Z is carbonyl, N, NR 65 Selected from O and S; R 65 These are independently hydrogen, C1-C8 alkyl, and C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 They are aryl and 5- to 10-membered heteroaryls.

[0082] "Heteroaralkyl" refers to an optionally substituted alkyl group, which is a subset of alkyl and heteroaryl groups as defined herein and is optionally substituted by an optionally substituted heteroaryl group.

[0083] A "carbocyclyl" or "carbocyclic" structure is a non-aromatic ring system with 3 to 10 ring carbon atoms ("C"). 3~10 This refers to a radical of a non-aromatic cyclic hydrocarbon group having 0 heteroatoms ("carbocyclyl"). In some embodiments, the carbocyclyl group has 3 to 8 ring carbon atoms ("C"). 3~8 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C"). 3~6 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C"). 3~6 Carbocyclyl). In some embodiments, the carbocyclyl group has 5 to 10 ring carbon atoms ("C"). 5~10 Carbocyclyl). Exemplary C 3~6 Examples of carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). 3~8 As for the carbocyclyl group, the above C 3~6Examples include the carbocyclyl group, 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). These are not limited to these. An example C 3~10 As for the carbocyclyl group, the above C 3~8 Carbocyclyl group, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C9) 10 ), spiro[4.5]decanil(C 10 Examples include, but are not limited to, the above. When the above examples are illustrated, in certain embodiments the carbocyclyl group may be monocyclic ("monocyclic carbocyclyl") or include fused, bridging, or spirocyclic systems (e.g., bicyclic systems ("bicyclic carbocyclyl")) and may be saturated or partially unsaturated. "Carbocyclyl" also includes cyclic systems in which a carbocyclyl ring as defined above is fused with one or more aryl or heteroaryl groups, where the bond site is on the carbocyclyl ring, and in such cases the number of carbons still refers to the number of carbons in the carbocyclic system. Unless otherwise specified, each presence of a carbocyclyl group may be independently substituted as needed, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments the carbocyclyl group may be unsubstituted C 3~10 It is a carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C 3~10 It is carbocyclyl.

[0084] In some embodiments, "carbocykrill" is a monocyclic saturated carbocykrill group having 3 to 10 ring carbon atoms ("C 3~10A cycloalkyl group is a ring carbon atom having 3 to 8 carbon atoms. In some embodiments, the cycloalkyl group has 3 to 8 carbon atoms. 3~8 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C"). 3~6 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 6 ring carbon atoms ("C"). 5~6 ("Cycloalkyl"). In some embodiments, the 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 C 5~6 Examples include cycloalkyl groups, as well as cyclopropyl (C3) and cyclobutyl (C4). 3~8 Examples of cycloalkyl groups include the above C 3~6 Examples include cycloalkyl groups, as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each cycloalkyl group is independently either unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, the cycloalkyl group is unsubstituted C 3~10 It is a cycloalkyl group. In certain embodiments, the cycloalkyl group is a substituted C 3~10 It is a cycloalkyl group.

[0085] A "heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system having a ring carbon atom 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 a heterocyclyl group containing one or more nitrogen atoms, the bond site can be a carbon or nitrogen atom, where the valence allows. A heterocyclyl group can be a monocyclic ring system ("monocyclic heterocyclyl"), a fused ring system, a bridging ring system, or a spiro-ring system (e.g., a bicyclic ring system ("bicyclic heterocyclyl")), and can be saturated or partially unsaturated. A heterocyclyl bicyclic ring system may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused with one or more carbocyclyl groups, where the binding site is located on the carbocyclyl or heterocyclyl ring, or on ring systems in which a heterocyclyl ring as defined above is fused with one or more aryl or heteroaryl groups, where the binding site is located on the heterocyclyl ring, in which case the number of ring members still refers to the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each presence of a heterocyclyl is independent and as needed. Substituted, i.e., either unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0086] In some embodiments, the heterocyclyl group is a 5-10 membered non-aromatic ring system having a ring carbon atom 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, the heterocyclyl group is a 5-8 membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5-6 membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclil has one or two ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclil has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0087] Examples of three-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxyranil, and thiorenyl. Examples of four-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanil, and thietanil. Examples of five-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranil, dihydrofuranil, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Examples of five-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanil, oxasulfuranil, disulfuranil, and oxazolidine-2-one. Examples of five-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Examples of six-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranil, dihydropyridinyl, and thianil. Examples of six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinil, dithianil, and dioxanil. Examples of six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanil. Examples of seven-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanil, oxepanil, and thiepanil. Examples of eight-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azokanil, oxekanil, and thiokanil. Examples of five-membered heterocyclyl groups condensed to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic rings) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranil, dihydrobenzothienyl, and benzoxazolinonil.Examples of six-membered heterocyclyl groups condensed to an aryl ring (also referred to herein as 6,6-bicyclic heterocyclic rings) include, but are not limited to, tetrahydroquinolinyl and tetrahydroisoquinolinyl.

[0088] The "nitrogen-containing heterocyclyl" group has at least one nitrogen atom, for example, but is not limited to morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), and This refers to 4- to 7-membered non-aromatic cyclic groups, including zethidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazine (e.g., N-methylpiperazine). Specific examples include azetidine, piperidone, and piperazone.

[0089] When "hetero" is used to describe a compound or a group present on a compound, it means that one or more carbon atoms in that compound or group are replaced by nitrogen, oxygen, or sulfur heteroatoms. Hetero can be applied to any of the hydrocarbyl groups listed above having 1 to 5, and especially 1 to 3, heteroatoms, such as alkyl, e.g., heteroalkyl; cycloalkyl, e.g., heterocyclyl; aryl, e.g., heteroaryl; cycloalkenyl, e.g., cycloheteralkenyl.

[0090] "Ashil" is -C(O)R 20 It refers to a radical, and here, R 20 This includes hydrogen, 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, as defined herein. "Alkanoyl" is R 20The group other than hydrogen is the acyl group. 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, and -C(O)-(CH2). t (C6-C 10 aryl), -C(O)-(CH2) t (5-10 member heteroaryl), -C(O)-(CH2) t (C3-C 10 Cycloalkyl) and -C(O)-(CH2) t Examples include, but are not limited to, (4- to 10-membered heterocyclines) (where t is an integer from 0 to 4). In a particular embodiment, R 21 C1-C8 alkyl groups substituted with halo or hydroxyl; or C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 These are aryl, arylalkyl, 5-10 membered heteroaryl, or heteroarylalkyl (each of which is substituted with an 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 It refers to the base, and here, R 29 These are substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted carbocyclyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heteroaryl groups. Certain alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Certain alkoxy groups are lower alkoxy groups, i.e., having 1 to 6 carbon atoms. Further specific alkoxy groups have 1 to 4 carbon atoms.

[0092] In a particular embodiment, R 29 is amino, substituted amino, C6~C 10 Aryl, aryloxy, carboxyl, cyano, C3~C 10 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, a group having 1-5 substituents, in particular 1-3 substituents, in particular 1 substituent. An example of a "substituted alkoxy" group is -O-(CH2) t (C6~C 10 aryl), -O-(CH2) t (5-10 member heteroaryl), -O-(CH2) t (C3~C 10 Cycloalkyl) and -O-(CH2) t (4-10 member heterocyclyls) are examples, but are not limited to these, where t is 0-4 Any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present is an integer of - and can itself be substituted with an 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] "Substituting amino acid" refers to the compound of the formula -N(R 38 ) refers to the amino group of 2, where R 38R is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or an amino protecting group, where R 38 At least one of them is not hydrogen. In a particular embodiment, each R 38 These are independently hydrogen, C1-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, and C6-C 10 Aryl, 5-10 member heteroaryl, 4-10 member heterocyclyl, or C3-C 10 Cycloalkyl; or C1-C8 alkyl substituted with halo or hydroxyl; C3-C8 alkenyl substituted with halo or hydroxyl; C3-C8 alkynyl substituted with halo or hydroxyl, or -(CH2) t (C6~C 10 Aryl), -(CH2) t (5-10 member heteroaryl), -(CH2) t (C3~C 10 Cycloalkyl) or -(CH2) t Selected from (4-10 member heterocyclyl), where t is an integer from 0 to 8, each of which is substituted with an 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 link together to form an alkylene group.

[0095] Examples of "substituted amino" groups include -NR 39 -C1~C8 alkyl, -NR 39 -(CH2) t (C6~C 10 Ariel), -NR 39 -(CH2) t (5-10 member heteroaryl), -NR 39 -(CH2) t (C3~C 10 Cycloalkyl) and -NR 39-(CH2) t Examples include (4-10 member heterocyclyls), but are not limited to these, where t is an integer from 0 to 4, for example, 1 or 2, and each R 39 The terms "substituted amino" independently represent H or C1-C8 alkyl; any alkyl group present may be substituted by a halo, substituted or unsubstituted amino or hydroxyl group; any aryl, heteroaryl, cycloalkyl or heterocyclyl group present may be substituted by an unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxyl group. To avoid misunderstanding, the term "substituted amino" includes alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino and substituted dialkylamino groups, as defined below. Substituted aminos include both monosubstituted and disubstituted amino groups.

[0096] "Carboxylate" 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 iodine(I). In certain embodiments, the 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 an alkyl group is replaced by a cycloalkyl group. Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl.

[0102] A "heterocyclylalkyl group" refers to an alkyl radical in which an alkyl group is substituted with a heterocyclyl group. Typical heterocyclylalkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, and morpholinylethyl.

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

[0104] Alkyl, alkenyl, alkynyl, carbocyrill, heterocyclyl, aryl, and heteroaryl groups as defined herein may be substituted as necessary (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyrill, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl groups). In general, the term "substituted" means, whether or not preceded by the term "as necessary," 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, produces a stable compound, e.g., a compound that does not undergo spontaneous transformation (e.g., rearrangement, cyclization, elimination, or other reactions). Unless otherwise indicated, a “substituted” group has substituents at one or more substituted positions on that group, and when two or more positions in any given structure are substituted, those substituents are either the same or different at each position. The term “substituted” is intended to include all acceptable substituents of an organic compound, substitution by any substituents described herein that form a stable compound. The present invention intends any and all such combinations to arrive at a stable compound. For the purposes of the present invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any preferred substituents, as described herein, that satisfy the bond valence of the heteroatom and consequently form a stable moiety.

[0105] Examples of carbon atom substituents include halogens, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, and -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 Alkenil, C 2~10 Alkinyl, C 3~10 Carbocyclyl, 3-14 member heterocyclyl, C 6~14 Examples include, but are not limited to, aryl and 5- to 14-membered heteroaryl groups, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R groups. dd Is it substituted with the base?

[0106] Alternatively, the two geminal hydrogens on a carbon atom form the group =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 of these beings is independent of C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenil, C 2~10 Alkinyl, C 3~10 Carbocyclyl, 3-14 member heterocyclyl, C 6~14 Selected from aryls and 5-14 member heteroaryls, or two R aa The groups are linked to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the base;

[0108] R bb Each of these entities exists independently as hydrogen, -OH, and -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 Alkenil, C 2~10 Alkinyl, C 3~10 Carbocyclyl, 3-14 member heterocyclyl, C 6~14Selected from aryls and 5-14 member heteroaryls, or two R bb The groups are linked to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the base;

[0109] R cc Each of these entities independently contains hydrogen and C. 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenil, C 2~10 Alkinyl, C 3~10 Carbocyclyl, 3-14 member heterocyclyl, C 6~14 Selected from aryls and 5-14 member heteroaryls, or two R cc The groups are linked to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the base;

[0110] R dd Each of these entities is independently 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 Alkenil, C 2~6 Alkinyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 Selected from aryls and 5-10 membered heteroaryls, where each alkyl, alkenyl, alkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg Substituted with; or two Geminal R ddSubstituents can combine to form either =O or =S;

[0111] R ee Each of these beings is independent of C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~10 Carbocyclyl, C 6~10 Selected from aryls, 3-10 membered heterocyclyls, and 3-10 membered heteroaryls, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg Substituted with the base;

[0112] R ff Each of these entities independently contains hydrogen and C. 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 Selected from aryls and 5-10 member heteroaryls, or two R ff The groups are linked to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. gg Substituted with the base;

[0113] R gg Each of these entities is independently: 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 Alkenil, C 2~6 Alkinyl, C 3~10 Carbocyclyl, C 6~10 It is either an aryl, a 3-10 membered heterocyclyl, a 5-10 membered heteroaryl; or two geminal Rs. gg Substituents can combine to form =O or =S; where X - It is a counterion.

[0114] A "counterion" or "anionic counterion" is a negatively charged group that associates with a cationic quaternary amino group to maintain electrical neutrality. Examples of counterions include halide ions (e.g., F - Cl - , Br - , I - ), NO3 - ClO4 - , OH - H2PO4 - HSO4 - SO4 -2Examples include 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, ethanolate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0115] Nitrogen atoms can be substituted or unsubstituted, wherever the bond valency allows, and may include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, and -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 Alkenil, C 2~10 Alkinyl, C 3~10 Carbocyclyl, 3-14 member heterocyclyl, C 6~14Examples include, but are not limited to, aryl and 5- to 14-membered heteroaryls, or two R atoms bonded to a nitrogen atom. cc The groups are linked together to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with R aa , R bb , R cc and R dd This is as defined above.

[0116] These and other exemplary substituents are described in detail in the detailed description, examples, and claims. The present invention is not intended to be limited by any means by the exemplary enumeration of substituents described above. Other definitions

[0117] The term "pharmaceutically acceptable salt" refers to a salt that, within reasonable limits of medical judgment, is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, or allergic reactions, and that meets a reasonable benefit-risk ratio. Pharmaceutically acceptable salts are well-known in this field. For example, Berge et al. published in J. Pharma. Pharmaceutically acceptable salts are described in detail in Ceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids, as well as inorganic and organic bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxyethanesulfonic acid. Examples include salts, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfons, 2-naphthalenesulfons, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectins, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyans, p-toluenesulfons, undecanoates, and valersates. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1~4Examples include alkyl)4 salts. Typical alkali metal salts or alkaline earth metal salts include salts of sodium, lithium, potassium, calcium, and magnesium. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cation salts formed with counterions (e.g., halide ions, hydroxide ions, carboxylate ions, sulfate ions, phosphate ions, nitrate ions, lower alkyl sulfonate ions, and aryl sulfonate ions) where appropriate.

[0118] The “subjects” to which the administration is intended include, but are not limited to, human (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 macaques, rhesus macaques), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs). In certain embodiments, the subject is human. In certain embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein.

[0119] Diseases, disorders, and conditions are used interchangeably in this specification.

[0120] As used herein, unless otherwise specified, the terms “treat,” “treating,” and “treatment” refer to 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 that delay or slow the progression of the disease, disorder, or condition ("therapeutic treatment"), and also refer to actions taken before a subject begins to suffer from a particular disease, disorder, or condition ("preventive treatment").

[0121] Generally, the “effective dose” of a compound refers to a sufficient amount to elicit a desired biological response. As will be understood by those skilled in the art, the effective dose of the compound in this invention may vary depending on factors such as the desired biological objective, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health status, and condition of the subject. The effective dose includes both therapeutic and prophylactic treatments.

[0122] Where used herein, unless otherwise specified, “therapeutic dose” of a compound means an amount sufficient to provide therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with that disease, disorder, or condition. “Therapeutic dose” of a compound means the amount of the therapeutic agent, alone or in combination with other treatments, that provides therapeutic benefit in the treatment of that disease, disorder, or condition. The term “therapeutic dose” may include an amount that improves the overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effect of another therapeutic agent.

[0123] As used herein, unless otherwise specified, “preventive dose” of a compound means an amount sufficient to prevent or prevent the recurrence of a disease, disorder, or condition, or one or more symptoms associated with that disease, disorder, or condition. The preventive dose of a compound means the amount of the therapeutic agent, alone or in combination with other agents, that provides a preventive benefit in the prevention of the disease, disorder, or condition. The term “preventive dose” may include an amount that improves overall prevention or enhances the preventive efficacy of another preventive agent. [Modes for carrying out the invention]

[0124] Detailed description of specific embodiments of the present 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, formulation suitability, stability, and / or safety compared to other oxysterols. compound

[0125] In one aspect, the present invention relates to formula (I): [ka] Characterized by the compound described or a pharmaceutically acceptable salt thereof, where R 1 C 1~6 It is alkyl; R 2 and R 3 Each of them independently contains hydrogen and C 1~6 Alkyl or carbocyric; or R 2 and R 3 These, together with the carbon atoms to which they are bonded, form a 3- to 8-membered ring; R 6 is either nonexistent or hydrogen; R 7 and R 8 Each of these independently consists of hydrogen, halogen, and C. 1~6 Alkyl or carbocyric; or R 7 and R 8 Each of them, together with the carbon atoms to which they are bonded, forms a 3- to 8-membered ring; or R 2 and R 7 These, together with the carbon atoms to which they are bonded, form a 3- to 8-membered ring; n is 1, 2, or 3; [ka] represents a single bond or a double bond, where one of them [ka] When it is a double bond, the other is [ka] It is a single bond; [ka] When one of them is a double bond, R 6 It does not exist.

[0126] In some embodiments, R 1 is substitution C 1~6 It is alkyl. In some embodiments, R 1 is unsubstituted C 1~6 It is alkyl. In some embodiments, R 1 R is methyl (e.g., -CHF2, -CH3, -CF3, -CH2OCH3 or -CH2OCH2CH3), ethyl, or isopropyl. In some embodiments, R 1 is -CH3. In some embodiments, R 1 It is ethyl.

[0127] In some embodiments, R 2 and R 3 Each of them independently contains hydrogen and C 1~6 It is alkyl or carbocyric, or R 2 and R 3 These, together with the carbon atoms to which they are bonded, form a 3- to 8-membered ring. In some embodiments, the 3- to 8-membered ring is a carbocykyl ring (e.g., cyclopropyl). In some embodiments, R 2 and R 3 Each of them independently contains hydrogen and C 1~6 It is alkyl or carbocyric. In some embodiments, R 2 and R 3Each of these 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 substitution C 1~6 It is alkyl. In some embodiments, R 2 is unsubstituted C 1~6 It is alkyl.

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

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

[0131] In some embodiments, R 3 These are 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 C 1~6 Alkyl (e.g., methyl (e.g., -CH3, -CF3), ethyl, isopropyl). In some embodiments, R 2 C 1~6 It is alkyl, R 3 C 1~6 It is alkyl. In some embodiments, R 2 and R 3 is -CH3. In some embodiments, R2 It is -CH3, and R 3 is -CF3. In some embodiments, R 2 It is -CH3, and R 3 is ethyl. In some embodiments, R 2 It is -CH3, and R 3 It is isopropyl.

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

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

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

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

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

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

[0139] In some embodiments, the compound of formula (I) is of formula (II): [ka] It is a compound of or a pharmaceutically acceptable salt of the compound.

[0140] In some embodiments, the compound of formula (II) is either formula (II-A) or formula (II-B): [ka] It is a compound of or a pharmaceutically acceptable salt of the compound.

[0141] In some embodiments, the compound of formula (I) is formula (II-Bi) or formula (II-B-ii): [ka] It is a compound of or a pharmaceutically acceptable salt of the compound.

[0142] In some embodiments, the compound of formula (I) is of formula (II-B-iii): [ka] It is a compound of or a pharmaceutically acceptable salt of the compound.

[0143] In some embodiments, the compound of formula (I) is formula (III): [ka] It is a compound of or a pharmaceutically acceptable salt of the compound.

[0144] In some embodiments, the compound of formula (III) is either formula (III-A) or formula (III-B): [ka] It is a compound of or a pharmaceutically acceptable salt of the compound.

[0145] In some embodiments, the compound of formula (III-B) is either of formula (III-C) or formula (III-D): [ka] It is a compound of or a pharmaceutically acceptable salt of the compound.

[0146] In some embodiments, the compound of formula (III-A) is formula (III-E) or formula (III-F): [ka] It is a compound of or a pharmaceutically acceptable salt of the compound.

[0147] In some embodiments, the compound of formula (III) is formula (III-Aia) or formula (III-Bia): [ka] It is a compound of or a pharmaceutically acceptable salt of the compound.

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

[0149] In some embodiments, R 2 and R 3 Each of them independently contains hydrogen and C 1~6 It is alkyl or carbocyric, or R 2 and R 3 These atoms, together with the carbon atoms to which they are bonded, form a 3- to 8-membered ring.

[0150] In some embodiments, R 2and R 3 Each of them independently contains hydrogen and C 1~6 It is alkyl or carbocyric.

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

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

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

[0154] In some embodiments, the compound is [ka] or selected from the group consisting of pharmaceutically acceptable salts thereof.

[0155] In some embodiments, the compound of formula (I) is of formula (IV): [ka] It is a compound of or a pharmaceutically acceptable salt of the compound.

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

[0157] In some embodiments, R2 and R 3 Each of them independently contains hydrogen and C 1~6 It is alkyl or carbocyric, or R 2 and R 3 These atoms, together with the carbon atoms to which they are bonded, form a 3- to 8-membered ring.

[0158] In some embodiments, R 2 and R 3 Each of them independently contains hydrogen and C 1~6 It is alkyl or carbocyric.

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

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

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

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

[0163] In some embodiments, the compound of formula (I) is of formula (V): [ka] It is a compound of or a pharmaceutically acceptable salt of the compound.

[0164] In some embodiments, the compound of formula (I) is of formula (VA): [ka] It is a compound of or a pharmaceutically acceptable salt of the compound.

[0165] In some embodiments, the compound of formula (I) is of formula (VB): [ka] It is a compound of or a pharmaceutically acceptable salt of the compound.

[0166] In some embodiments, the compound of formula (III) is formula (VC) or formula (VD): [ka] It is a compound of or a pharmaceutically acceptable salt of the compound.

[0167] In some embodiments, the compound of formula (I) is of formula (VE): [ka] It is a compound of or a pharmaceutically acceptable salt of the compound.

[0168] In some embodiments, the compound of formula (VE) is of formula (VEi): [ka] It is a compound of or a pharmaceutically acceptable salt of the compound.

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

[0170] [ka] The compound or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is [ka] [ka] [ka] [ka] or selected from pharmaceutically acceptable salts thereof. Pharmaceutical composition

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

[0172] The compounds provided herein, when used as pharmaceuticals, are typically administered in the form of pharmaceutical compositions. Such compositions may be prepared in ways well known in the pharmaceutical field and contain at least one active compound.

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

[0175] Generally, the compounds provided herein are administered in effective doses. The actual amount of compound administered is typically determined by a physician in light of the relevant circumstances, including the symptoms being treated, the chosen route of administration, the specific compound administered, the individual patient's age, weight and response, and the severity of the patient's symptoms.

[0176] The pharmaceutical compositions provided herein may be administered by various routes, including oral, rectal, percutaneous, subcutaneous, intravenous, intramuscular, and intranasal. Depending on the intended route of delivery, The compounds provided in this specification 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 a bulk liquid solution or suspension or a bulk powder. However, more generally, compositions are provided in unit dosage forms to facilitate precise administration. The term “unit dosage form” refers to a physically discontinuous unit suitable as a unit dose 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 pharmaceutically acceptable excipients. Typical unit dosage forms include pre-measured and pre-filled ampoules or syringes for liquid compositions, or pills, tablets, capsules, etc., for solid compositions. In such compositions, the compound is usually present in small amounts (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 non-aqueous vehicle containing buffers, suspending agents and dispensing agents, colorants, flavorings, etc. Solid forms may include, for example, any of the following components or compounds of similar properties: binders (e.g., microcrystalline cellulose, tragacanth gum or gelatin); excipients (e.g., starch or lactose); disintegrants (e.g., alginic acid, Primogel or corn starch); lubricants (e.g., magnesium stearate); lubricants (e.g., colloidal silicon dioxide); sweeteners (e.g., sucrose or saccharin); or flavorings (e.g., peppermint, methyl salicylate or orange flavor).

[0179] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As is conventional, the active compound in such compositions is typically a trace component, often about 0.05–10% by weight, with the remainder being the injectable carrier, etc.

[0180] Transdermal compositions are typically formulated as topical ointments or creams, usually containing one or more active ingredients in an amount ranging from about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredients are typically miscible with a paraffin ointment base or a water-miscible ointment base. Alternatively, the active ingredients may be formulated as a cream, for example, containing an oil-in-water cream base. Such transdermal formulations are well known in the art and generally include further components that enhance the skin penetration or stability of the active ingredient or the formulation. All such known transdermal formulations and components are included within the scope provided herein.

[0181] The compounds provided herein may also be administered by transdermal devices. Therefore, transdermal administration can be achieved using reservoir-type, porous membrane-type, or solid matrix-type patches.

[0182] The components described above for orally, injectably, or topically administered compositions are merely representative. Other materials and processing methods are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania (as incorporated herein by reference).

[0183] For orally administered compositions, injectable compositions or topically administered compositions The components listed above are representative only. Other materials and processing methods are shown in Part 8 of Remington's *The Science and Practice of Pharmacy*, 21st edition, 2005, Publisher: Lippincott Williams & Wilkins (as incorporated herein by reference).

[0184] The compounds of the present invention may also be administered in sustained-release form or via sustained-release drug delivery systems. A description of typical sustained-release materials can be found in Remington's Pharmaceutical Sciences.

[0185] The present invention also relates to pharmaceutically acceptable formulations of the compound 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, each comprising 6, 7, and 8 α-1,4-linked glucose units, respectively, with one or more substituents optionally on the bonded sugar moiety (including, but not limited to, methylation, hydroxyalkylation, acylation, and sulfoalkyl ether substitution). In a particular embodiment, the cyclodextrin is sulfoalkyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol®. See, for example, U.S. Patent No. 5,376,645. In a particular embodiment, 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 pharmaceutically acceptable acid addition salts of the compound of formula (I). Acids that can be used to prepare pharmaceutically acceptable salts are those that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions (e.g., hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, p-toluenesulfonate, etc.).

[0187] The following examples illustrate typical pharmaceutical compositions that can be prepared according to the present invention. However, the present invention is not limited to the following pharmaceutical compositions.

[0188] Exemplary Formulation 1 - Tablets: The compound of formula (I) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a dry gelatin binder in a weight ratio of approximately 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is formed in a tablet press into 240-270 mg tablets (80-90 mg of the active compound per tablet).

[0189] Exemplary Formulation 2 - Capsules: The compound of formula (I) or a pharmaceutically acceptable salt thereof may be mixed with a starch diluent in a weight ratio of approximately 1:1 as a dry powder. The mixture is filled into 250 mg capsules (125 mg of the active compound per capsule).

[0190] Exemplary Formulation 3 - Liquid Formulation: A compound of formula (I) or a pharmaceutically acceptable salt thereof (125 mg) may be mixed with sucrose (1.75 g) and xanthan gum (4 mg), the resulting mixture may be mixed and passed through a No. 10 mesh US sieve, and then mixed with an aqueous solution of previously prepared microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50 mg). Sodium benzoate (10 mg), fragrance and colorant are diluted with water and added while stirring. Then, to a total volume of 5 mL Sufficient water may be added.

[0191] Exemplary Formulation 4 - Tablets: The compound of formula (I) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a dry gelatin binder in a weight ratio of approximately 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is formed in a tablet press into tablets of 450-900 mg (150-300 mg of the active compound).

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

[0193] Exemplary Formulation 6 - Tablets: The compound of formula (I) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a dry gelatin binder in a weight ratio of approximately 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is formed in a tablet press into 90-150 mg tablets (30-50 mg of the active compound per tablet).

[0194] Exemplary Formulation 7 - Tablets: The compound of formula (I) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a dry gelatin binder in a weight ratio of approximately 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is formed in a tablet press into 30-90 mg tablets (10-30 mg of the active compound per tablet).

[0195] Exemplary Formulation 8 - Tablets: The compound of formula (I) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a dry gelatin binder in a weight ratio of approximately 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is formed in a tablet press into 0.3 to 30 mg tablets (0.1 to 10 mg of the active compound per tablet).

[0196] Exemplary Formulation 9 - Tablets: The compound of formula (I) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a dry gelatin binder in a weight ratio of approximately 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is formed in a tablet press into 150-240 mg tablets (50-80 mg of the active compound per tablet).

[0197] Exemplary Formulation 10 - Tablets: The compound of formula (I) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a dry gelatin binder in a weight ratio of approximately 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is formed in a tablet press into 270-450 mg tablets (90-150 mg of the active compound per tablet).

[0198] The dose levels of the injectable agent range from approximately 0.1 mg / kg / hour to at least 10 mg / kg / hour, all over a period of approximately 1 to 120 hours, particularly 24 to 96 hours. Preloading bolus of approximately 0.1 mg / kg to 10 mg / kg or more may also be administered to achieve an appropriate steady-state level. The maximum total dose is not expected to exceed approximately 2 g / day for human patients weighing 40-80 kg.

[0199] For the prevention and / or treatment of long-term symptoms, the regimen for treatment usually extends for months or even years, so oral administration is preferred for patient convenience and tolerance. For oral administration, a typical regimen is 1 to 5 times per day, particularly 2 to 4 times, and typically 3 times per day. When using these dosing patterns, each dose yields approximately 0.01 to approximately 20 mg / kg of the compound provided herein, with preferred doses yielding approximately 0.1 to approximately 10 mg / kg, particularly approximately 1 to approximately 5 mg / kg.

[0200] Transdermal doses are generally similar to or lower than the levels achieved using injectable doses. Selected to provide a sufficient blood level.

[0201] When used to prevent the development of CNS disorders, the compounds provided herein may typically be administered to subjects at risk of developing the symptoms at the dosage levels described above, with the advice and supervision of a physician. Subjects at risk of developing specific symptoms generally include those with a family history of the symptoms or those identified by genetic testing or screening as particularly susceptible to developing the symptoms. Treatment method and usage method

[0202] The compounds of the present invention (e.g., compounds of formula (I) as described herein and their pharmaceutically acceptable salts) are typically designed to modulate the function of NMDA and therefore act as oxysterols for the treatment and prophylaxis of CNS-related symptoms in subjects, for example. In some embodiments, the compounds of the present invention (e.g., compounds of formula (I) as described herein and their pharmaceutically acceptable salts) are typically designed to cross the blood-brain barrier (e.g., designed to be transported across the blood-brain barrier). Modulation, as used herein, refers to, for example, inhibition or enhancement of the function of NMDA receptors. In certain embodiments, compounds of formula (I) or their pharmaceutically acceptable salts may act as negative allosteric modulators (NAMs) of NMDA and inhibit the function of NMDA receptors. In certain embodiments, the present invention, e.g., compounds of formula (I) or their pharmaceutically acceptable salts, may act as positive allosteric modulators (PAMs) of NMDA and enhance the function of NMDA receptors. In certain (ceratin) embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof modulates the function of NMDA, but does not act as either 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 sterol synthesis disorder. In some embodiments, the disorder is gastrointestinal (GI) disorder, e.g., constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) (e.g., ulcerative colitis, Crohn's disease), structural disorders affecting 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-Lemle-Oppitz syndrome (SLOS). In some embodiments, the disorder is desmosterosis. In some embodiments, the disorder is sitosterolemia. In some embodiments, the disorder is cerebral tenosynovitis 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 symptoms related to NMDA regulation 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 GI, anal disorders (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas), colon polyps, cancer, colitis, and CNS symptoms, such as those described herein.

[0206] Exemplary CNS symptoms associated with NMDA regulation include adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, social phobia, and generalized anxiety disorder), cognitive impairments (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, and suicidal ideation), schizophrenia or other psychotic disorders (including schizoaffective disorder), sleep disorders (including insomnia), substance abuse-related disorders, and personality disorders (including obsessive-compulsive personality disorder). Examples of conditions that may be affected include, but are not limited to, autism spectrum disorder (including those involving mutations in Shank group proteins (e.g., Shank3)), neurodevelopmental disorders (including Rett syndrome), multiple sclerosis, sterol synthesis disorders, pain (acute and chronic pain; headaches, including migraines), paroxysmal disorders (including status epilepticus and monogenotype epilepsy, including Dravet disease and tuberous sclerosis syndrome (TSC)), stroke, traumatic brain injury, motor disorders (including Huntington's disease and Parkinson's disease), and tinnitus. In certain embodiments, compounds of the present invention, for example, compounds of formula (I) or pharmaceutically acceptable salts thereof, may be used to induce sedation or anesthesia. In certain embodiments, compounds of formula (I) or pharmaceutically acceptable salts thereof are useful in the treatment or prevention of adjustment disorders, anxiety disorders, cognitive impairments, dissociative disorders, eating disorders, mood disorders, schizophrenia or other psychotic disorders, sleep disorders, substance-related disorders, personality disorders, autism spectrum disorders, neurodevelopmental disorders, sterol synthesis disorders, pain, paroxysmal disorders, stroke, traumatic brain injury, motor and visual impairments, 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 context, a method is provided for treating or preventing cerebral excitability in a subject who is prone to or suffering from symptoms related to cerebral excitability, the method comprising administering to the subject an effective amount of the compound of the present invention, for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0208] In another aspect, the present invention provides combinations of the compounds of the present invention, for example, the compound of formula (I) or a pharmaceutically acceptable salt thereof, with another pharmacologically active substance. The compounds provided herein may be administered as the sole active substance or in combination with other substances. Combination administration may be carried out by any method apparent to those skilled in the art, including, for example, separate administrations, sequential administrations, simultaneous administrations, and alternating administrations. Diseases and Disabilities 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 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 disorders is described herein. Cholesterol has essential rules in growth and development. Cholesterol is a membrane lipid and a precursor to many molecules that play important roles in cell growth and differentiation, protein glycosylation, and signaling pathways. Several enzymes and intermediates are involved in cholesterol biosynthesis. A deficiency in any of the enzymes involved in cholesterol biosynthesis leads to the accumulation of intermediates and biomolecular imbalances, resulting in disorders including congenital skeletal malformations, dysmorphic facial features, psychomotor retardation, and growth retardation. In one embodiment, sterol synthesis disorders or the symptoms of sterol synthesis disorders are defined as sterol synthesis disorders. Subjects suffering from this condition may be treated by administering the compounds described herein (e.g., NMDA receptor modulating compounds as described herein). Further complications are described below. Smith-Lemle-Oppitz syndrome

[0210] In one aspect, methods for treating Smith-Lemle-Oppitz syndrome (or SLOS, or 7-dehydrocholesterol reductase deficiency) are described herein. SLOS is a congenital anomaly of cholesterol synthesis. In addition to microcephaly, moderate to severe intellectual disability, sensory hypersensitivity, stereotypic behavior, dysmorphic facial features, and syndactyly of the second and third toes, a characteristic feature of this disorder is low levels of cerebrosterol (24(S)-hydroxycholesterol). SLOS is an autosomal recessive genetic disorder resulting from a deficiency of the last enzyme in the cholesterol synthesis pathway, causing low or low to normal levels of plasma cholesterol as well as 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; as well as reducing the accumulation of 7DHC and 8DHC, which are potentially toxic cholesterol precursors. Desmosterosis

[0211] Desmosterosis is a deficiency of desmostor reductase and has a phenotype similar to SLOS. In one aspect, a method for treating desmosterosis with compounds described herein is 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 increases the absorption of plant sterols and cholesterol from the intestines. Patients typically present with tendon xanthomas and nodular xanthomas, as well as premature coronary artery disease. In one aspect, methods for treating sitosterolemia with compounds described herein are described herein. Cerebral Tendon Xanthomatosis (CTX)

[0213] In one aspect, a method for treating cerebral xanthomatous cerebrospinal fluid (also known as cerebral cholesterol deposition or Van Bogaert-Scherer-Epstein syndrome) with compounds described herein is described herein. CTX may 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) that are important in the absorption of fats in the intestines. Dysfunction of this enzyme can lead to cholesterol accumulation in tissues. CTX is characterized by diarrhea in children and cataracts, tendon xanthomatous cerebrospinal fluid, reduced mental capability, and abnormal motor skills in adults. Mevalonate kinase deficiency syndrome (MKD)

[0214] Mevalonate kinase deficiency (also known as mevalonateuria (a more severe form of MKD), or hyper-IgD syndrome with periodic fever syndrome (HIDS, i.e., hyperglobulin Demia) (a more benign form of MKD)) is caused by insufficient activity of mevalonate kinase, resulting in the accumulation of mevalonate in the urine. MKD can result in growth retardation, hypotonia, anemia, hepatosplenomegaly, dysmorphic features, intellectual disability, and general growth retardation. Mevalonateuria is a condition in which the body It is characterized by delayed physical and mental development, growth retardation, recurrent episodes of fever with vomiting and diarrhea, enlargement of the liver, spleen, and lymph nodes, microcephaly (small head size), cataracts, hypotonia, short stature, distinctive facial features, ataxia, and anemia. HIDS is characterized by recurrent episodes of fever with lymph node enlargement, arthralgia, gastrointestinal problems, and rash. In one aspect, a method for treating MKD with compounds described herein is 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). SC4MOL deficiency is characterized by the accumulation of dimethylsterols and monomethylsterols, which can be detected in blood, skin flakes, or primary dermal fibroblasts. In one aspect, methods for treating SC4MOL deficiency with compounds described herein are described herein. Niemann-Pick disease

[0216] Niemann-Pick disease is a lysosomal storage disorder caused by a gene mutation that affects metabolism. Niemann-Pick disease results in the body's inability to transport cholesterol and other fatty substances (lipids), leading to their abnormal accumulation. This accumulation damages the affected tissue. autism

[0217] In one context, methods for treating autism spectrum disorder or autism are described herein. Autism spectrum disorder (ASD) and autism refer to a group of complex disorders of brain development. Autism is typically characterized by difficulties in social interaction, such as verbal and nonverbal communication. Individuals with autism often exhibit repetitive behaviors. Autism may be accompanied by intellectual disability, motor coordination and attention difficulties, and physical health problems, such as sleep disturbances and gastrointestinal problems. Individuals with autism may also excel in visual skills, music, mathematics, and arts. Autism may refer to autism spectrum disorder, childhood disintegrative disorder, pervasive developmental disorder not otherwise specified (PDD-NOS), and Asperger's syndrome. Autism also refers to autism caused by a single gene, such as synaptopathy, including Rett syndrome, fragile X syndrome, and Angelman syndrome. Disorders associated with phenylketonuria

[0218] In one aspect, methods for treating disorders associated with phenylketonuria (e.g., cognitive impairment) with compounds described herein are described herein. Phenyletonuria can lead to hypocholesterolemia and hypovitamin D status. Total cholesterol and low-density cholesterol, as well as 25-hydroxyvitamin D, were found to be decreased in subjects with phenylketonuria compared to subjects without phenylketonuria (Clin.Chim.Acta 2013, 416:54-59). 24S-hydroxycholesterol, 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 24S-OHC and 7β-hydroxycholesterol levels correlate with phenylalanine levels, and 27S-hydroxycholesterol levels may correlate with 25-hydroxyvitamin D levels in subjects with phenylketonuria. abbreviated form

[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: Des-Martin-Periodinane; Depositphotos: Ethyl acetate; TEA: Triethylamine; AlaOH: Alanine; Boc: t-Butoxycarbonyl. Py: Pydidine; 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] For the purpose of enabling a better understanding of the invention as described herein, the following examples are provided. The synthetic and biological examples described herein are provided to illustrate the compounds, pharmaceutical compositions and methods provided herein and should not be construed as limiting their scope.

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

[0222] Example 1. Synthesis of Compound 1 [ka] Step 1. Dess-Martin reagent (1.09 g, 2.59 mmol) was added in small portions to a solution of reaction product A1 (700 mg, 1.73 mmol) in anhydrous CH2Cl2 (5 mL) at 0°C. The reaction mixture was stirred at 25°C for 3 hours. The mixture was quenched with saturated NaHCO3 / Na2S2O3 aqueous solution (1:3, 15 mL) and extracted with ethyl acetate (2 × 50 mL). The organic phase was then washed with brine (50 mL), dried over Na2SO4, and concentrated to obtain 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), a solution of AlMe3 (2.61 mL, 5.22 mmol) (2 M in toluene) was added at 25°C. The resulting mixture was stirred at 25°C for 1 hour, and then a solution of A2 (700 mg, 1.74 mmol) in toluene (5 mL) was added under nitrogen at -78°C. The mixture was stirred for a further 30 minutes, 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 hours, and then quenched with saturated NH4Cl aqueous solution (30 mL) at -78°C. The resulting suspension was filtered, and the filter cake was washed with dimethyl phosphate (2 × 50 mL). The combined organic phases were dried over Na2SO4, concentrated, and purified over silica gel (PE / dimethyl = 10 / 1 to 8 / 1) to obtain 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 minute chromatography, 10⁻⁸ AB), C 28 H 49 O2[M+H] + MS ESI calculation value 417, C 28 H 45 [M-2H2O+H] + The 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  (10 mL), Pd / C (50 mg) was added. The reaction mixture was stirred at 50°C for 12 hours under hydrogen (50 psi), and then filtered through a Celite pad. The filtrate was concentrated under reduced pressure, and the resulting residue was purified with silica gel (PE /  = 10 / 1) to obtain both compound 2 (5 mg, 9%) and compound 3 (47.8 mg, 87%) as off-white solids. 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-minute chromatography). Fee, 10-80AB), C 28 H 51 O2[M+H] + MS ESI calculation value 419, C 28 H 47[M-2H2O+H] + The measured value is 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 minute chromatography, 10⁻⁸ AB), C 28 H 51 O2[M+H] + MS ESI calculation value 419, C 28 H 47 [M-2H2O+H] + The measured value is 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 hours. This mixture was cooled in ice water. The precipitated solid was filtered off and washed with excess water to obtain 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), 98% H2SO4 (2.80 g, 28.1 mmol) was added. This mixture was stirred at 25°C for 24 hours. The reaction mixture was evaporated under reduced pressure. The distillate was washed with water (20 mL). The organic layer was separated and dried over Na2SO4 to obtain 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 minutes, A3 (20 g, 63.1 mmol) was added. The resulting mixture was stirred at 60°C for 4 hours. This reaction mixture was poured into ice water (500 mL) and extracted with ethyl acetate (2 × 500 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / ethyl acetate = 15 / 1) to obtain 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), Ac2O (8.75 g, 85.8 mmol) and DMAP (13.9 g, 114 mmol) were added. This mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with water (200 mL) and extracted with DCM (3 × 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 obtain A5 (20 g, 99%) as an off-white solid. Step 5. Under a nitrogen atmosphere, 9-BBN (0.5 M in THF, 185 mL, 92.5 mmol) was added to a solution of A5 (30 g, 84.1 mmol) in anhydrous THF (150 mL) at 30°C. This mixture was stirred at 75°C for 3 hours. 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 hours. The reaction product was cooled, quenched with water (300 mL), and extracted with RINKAN (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 obtain A6 (20g, 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. AcCl (2.82 g, 36.0 mmol) was added to a suspension of A6 (20 g, 45.1 mmol) in anhydrous MeOH (250 mL). This mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated to remove most of the MeOH, diluted with Depositphotos (500 mL), washed with saturated NaHCO3 (500 mL) and brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / Depositphotos / DCM = 8 / 1 / 1) to obtain 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), 5% Pt / C (2 g) was added. This mixture was degassed and purged with H2 several times, and stirred under an H2 balloon at 25°C for 4 hours. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated to obtain 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. DMP (85.2 g, 201 mmol) was added to a solution of A8 (27 g, 67.0 mmol) in DCM (300 mL) at 25°C. The reaction mixture was stirred at 25°C for 1 hour. The mixture was poured into saturated Na2S2O3 (400 mL) at 0°C and extracted with ELISA (3 × 300 mL). The combined organic layers were washed with saturated NaHCO3 (2 × 250 mL) and brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain A9 (27 g, crude) as an oil, which was used directly for the next step without further purification. Step 9. AlMe3 (100 mL, 201 mmol, 2 M in toluene) was added dropwise to a solution of BHT (88.8 g, 403 mmol) in toluene (250 mL) at a temperature below 25°C. This solution was stirred at 25°C for 1 hour. 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 hour, 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 hours. This reaction was quenched with a saturated citric acid solution (400 mL) at -78°C. After stirring at 25°C for 0.5 hours, the resulting mixture was filtered, and the filtrate was filtration with siRNA. Extraction (3 × 300 mL). The combined organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. This crude product was purified by silica gel column (PE / siRNA = 5 / 1) to obtain the product (18.5 g, 66%), and 70 mg of this product was recrystallized (PE / siRNA = 10 mL / 2 mL) to obtain 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 minute chromatography, 10⁻⁸ AB), C 27 H 43 O2[M+H-H2O] + The MS ESI calculated value is 399, and the measured value is also 399. Step 10. To a solution of LiAlH4 (6.11 g, 161 mmol) in THF (135 mL), a solution of A27 (27 g, 64.8 mmol) in THF (135 mL) at 0°C was added dropwise. This mixture was stirred at 25°C for 1 hour. H2O (100 mL) was added at 0°C. The reaction mixture was filtered and washed with THF (2 × 100 mL). The filtrate was concentrated under reduced pressure to obtain the crude product, which was washed with SiO (100 mL) to obtain compound 4 (25 g, 100%). 30 mg of this product was recrystallized (SiO, 3 mL) to obtain 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 Chromatography for minutes, 10-80 AB), C 26 H 45 O2[M+H] + MS ESI calculation value 389, C 26 H 43 The measured value of O[M+H-H2O] is 371. Step 11. DMP (58.5 g, 138 mmol) was added at 0°C to a solution of compound 4 (180 mL) in DCM (180 mL). The reaction mixture was stirred at 25°C for 1 hour. This mixture was poured into saturated Na2S2O3 (100 mL) at 0°C. This mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with saturated NaHCO3 (2 × 150 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column (PE / ethyl acetate = 5 / 1) to obtain 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), MeMgBr (51 mL, 154 mmol) was added under N2 at 0°C. The reaction mixture was stirred at 25°C for 1 hour. The reaction was quenched with saturated NH4Cl (30 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This was purified by silica gel column chromatography (PE / ethyl acetate = 10 / 1) to obtain 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 obtain 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-minute chromatography, 30-90AB), C 27 H 47 O2[M+H] + MS ESI calculation value 403, C 27 H 45 O[M-H2O+H] + The 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 minute chromatography, 30-90 AB), C 27 H 47 O2[M+H] + MS ESI calculation value 403, C 27 H 45 O[M-H2 O+H] + The measured value was 385.

[0225] Example 4. Synthesis of Compounds 7 and 8 [ka] Step 1. DMP (11.3g, 26.8mmol) was added to a solution of A11 (3.6g, 8.94mmol) in DCM (40mL) at 0°C. The reaction mixture was stirred at 25°C for 1 hour. This mixture was poured into saturated Na2S2O3 (60mL) at 0°C and extracted with ethyl acetate (3×50mL). The combined organic layers were washed with saturated NaHCO3 aqueous solution (2×50mL) and brine (50mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This was purified by silica gel column (PE / ethyl acetate = 15 / 1) to obtain A13 (1.4g, 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) under N2 at -10°C, EtMgBr (3 M in diethyl ether, 1.43 mL, 4.30 mmol) was added dropwise. This mixture was stirred at 25°C for 3 hours. This mixture was quenched with saturated NH4Cl (10 mL) and extracted with ELISA (3 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluted with DCM to obtain 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 obtain 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 minutes (2 minutes chromatography, 30-90AB), C 29 H 51 O2[M+H] + MS ESI calculation value 431, C 29 H 47 [M+H-2H2O] + The 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 minutes (2 minutes chromatography, 30-90AB), C 29 H 51 O2[M+H] + MS ESI calculation value 431, C 29 H 47 [M+H-2H2O] + The 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) under N2 conditions at 0°C, 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 hours. The reaction mixture was cooled to 0°C, quenched with saturated NH4Cl (10 mL), and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM / acetone = 500 / 1) to obtain 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 μm; mobile phase: supercritical CO2 / EtOH + NH3H2O ​​= 65 / 35; flow rate: 60 ml / min; wavelength: 220 nm) to obtain 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 minutes (2 minutes chromatography, 30-90AB), C 30 H 53 O2[M+H] + MS ESI calculation 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 minute chromatography, 30-90AB), C 30 H 53 O2[M+H] + MS ESI calculation value 445, C 30 H 49 [M+H-2H2O] + Actual measured 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), TMSCF3 (106 mg, 0.748 mmol) was added at 25°C. The reaction mixture was stirred at 25°C for 1 hour. TBAF (271 mg, 1.04 mmol) was added at 25°C. The reaction mixture was poured into water and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with saturated NaHCO3 (2 × 20 mL) and brine (20 mL), and Na2 The material was dried with SO4, filtered, and concentrated under reduced pressure to obtain 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 obtain 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 minutes chromatography, 3 0-90AB), C 28 H 44 F3O[M-H2O+H] + MS ESI calculated value 453, measured 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 0.31 - 0.87 (m, 19H), 0.68 (s, 3H). LCMS Rt = 1.320 min (2-minute chromatogram) Tography, 30-90AB), C 28 H 44 F3O[M-H2O+H] + The MS ESI calculated value is 453, and the measured value is also 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), TMSCF3 (365 mg, 2.57 mmol) was added at 25°C. This mixture was stirred at 25°C for 1 hour. TBAF (806 mg, 3.09 mmol) was added. This mixture was stirred at 25°C for 1 hour. This mixture was poured into water (30 mL), washed with saturated brine (2 × 20 mL), dried over Na₂SO₄, and concentrated under reduced pressure to obtain 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 minute chromatography, 30-90 AB), C 27 H 42 F3O[M-H2O+H] + The MS ESI calculated value is 439, and the measured value is also 439. Step 2. A20 (190 mg, 0.416 mmol) was purified at 25°C by SFC (column: Chiralpak AD 250 × 30 mm ID, 5 μm; mobile phase: supercritical CO2 / MeOH + NH3H2O ​​= 65 / 35; flow rate: 60 ml / min; wavelength: 220 nm) to obtain 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 mins (2 minutes chromatography, 30-90 AB), C 27 H 44 F3O2[M+H] + MS ESI calculation value 457, C 27 H 42 F3O[M+H-H2O] + The measured 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 minute chromatography, 30-90AB), C 27 H 44 F3O2[M+H] + MS ESI calculation value 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 hours. The reaction mixture was quenched with brine (15 mL), diluted with ethyl acetate (20 mL), filtered through a Celite pad, and the filtrate was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / ethyl acetate = 20 / 1) to obtain 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-minute chromatography, 30-90AB), C 28 H 47 O2[M+H] + MS ESI calculation value 415, C 28 H 45 O[M+H-H2O] + The measured value was 397.

[0230] Example 9. Synthesis of compounds 18, 19, and 20 [ka] Step 1. DMP (2.94 g, 6.94 mmol) was added to a solution of A8 (1.4 g, 3.47 mmol) in DCM (20 mL) at 25°C. This mixture was then heated at 25°C. The mixture was stirred for 2 hours. This mixture was poured into saturated Na2S2O3 (100 ml) at 0°C and extracted with SiO2 (2 × 100 mL). The combined organic layers were washed with saturated NaHCO3 (2 × 80 mL) and brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain 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), AlMe3 (5.60 mL, 2 M in toluene, 11.2 mmol) was added dropwise at 0°C. The reaction mixture was stirred at 25°C for 1.5 hours. 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 hour. EtMgBr (3.73 mL, 3.0 M in diethyl ether, 11.2 mmol) was added at -70°C. The reaction mixture was stirred for a further 1 hour at -70°C. This reaction was quenched with NH4Cl (100 mL) and extracted with SiO2 (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 obtain the crude product. This was purified by silica gel chromatography using PE / siRNA = 10 / 1 elution to obtain 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), MeLi (3.17 mL, 5.08 mmol) at -70°C was added. This mixture was stirred at -70°C for 10 minutes. This reaction was quenched with saturated NH4Cl (20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. This mixture was combined with another batch synthesized from 50 mg of the starting material. The residue was purified by silica gel chromatography (PE / ethyl acetate = 10 / 1) to obtain 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 minutes chromatography, 30-90AB), C 29 H 51 O2[M+H] + MS ESI calculation value 431, C 29 H 47 [M+H-2H2O] + The measured value was 395. Step 4. To a solution of compound 18 (200 mg, 0.464 mmol) in ethyl acetate (10 mL), Pd / C (100 mg) was added at 25 °C. This mixture was stirred under H2 at 55 °C for 12 hours. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (2 × 40 mL). This mixture was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel chromatography with PE / ethyl acetate = 10 / 1 elution to obtain 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 minutes chromatography, 30-90AB), C 29 H 53 O2[M+H] + MS ESI calculation value 433, C 29 H 49 [M+H-2H2O] + The 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 calculation value 433, C 29 H 49 [M+H-2H2O] + The measured value was 397.

[0231] Example 10. Synthesis of Compound 22 [ka] Step 1. Pd / C (10%, 600 mg) was added to a solution of A7 (3 g, 7.48 mmol) in THF (30 mL). This mixture was degassed and purged with H2 three times. The resulting mixture was stirred under H2 at 25°C for 16 hours. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated to obtain 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 (3g, 7.41 mmol) in DCM (30 mL), PCC (3.19 g, 14.8 mmol) and silica gel (4 g, 66.6 mmol) were added at 25°C. This mixture was stirred at 25°C for 1.5 hours. This mixture was filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE / siRNA = 50 / 1 to 10 / 1) to obtain 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), AlMe3 (8.9 mL, 17.8 mmol, 2 M in toluene) was added under N2 conditions at 0°C. This mixture was stirred at 25°C for 1 hour. A solution of A33 (2.4 g, 5.96 mmol) in toluene (5 mL) at -70°C was added. This mixture was stirred at -78°C for 1 hour. MeMgBr (5.93 mL, 17.8 mmol, 3 M in diethyl ether) was added at -78°C. This mixture was stirred at -78°C for 1 hour. This reaction mixture was quenched with saturated citric acid (100 mL). This mixture was extracted with HCl (3 × 100 mL), washed with brine (3 × 300 mL), dried over Na₂SO₄, concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (PE / HCl = 30 / 1 to 10 / 1) to obtain 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 mins (2-minute chromatography, 30-90 AB), C 27 H 47 O2[M+H] + MS ESI calculation value 418.3, [M+H-H2O] + The measured value was 401. Step 4. EtMgBr (3M diethyl ether, 713 μL, 2.14 mmol) was added to a solution of A34 (300 mg, 0.716 mmol) and Ti(i-PrO)4 (203 mg, 0.716 mmol) in THF (10 ml). This mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched with saturated NH4Cl (5 mL). This mixture was filtered through a Celite pad. The filtrate was extracted with SiO2 (2 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / SiO2 = 20 / 1 to 10 / 1). Compound 22 (77 mg, 26%) was obtained as an off-white solid. 1 1H 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 minutes (2 minutes chromatography, 30-90AB), C 28 H 49 O2[M+H] + MS ESI calculation value 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), Pd / C (10% wt, 26.6 mg, 24.8 mmol) was added. After degassing three times with H2, the reaction mixture was stirred under H2 (55 Psi) at 50°C for 72 hours. The reaction product was filtered, and the filtrate was concentrated to obtain the crude product, which was purified by silica gel column (PE / Â=15 / 1) to obtain 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 0.4 Hz, 3H), 0.64 (s, 3H). LCMS Rt=1.293 min (2.0 min chromatography, 30-90 AB), C 27 H 49 O2[M+H] + MS ESI calculation value 405, C 27 H 45 [M-2H2O+H] + The 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 minutes (2.0 minutes chromatography, 30-90AB), C 27 H 49 O2[M+H] + MS ESI calculation value 405, C 27 H 45 [M-2H2O+H] + The 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), Ph3PMeBr (2.66 g, 7.47 mmol) was added at 60°C. This mixture was stirred at 60°C for 1 hour. A13 (1 g, 2.49 mmol) was added at 60°C. This mixture was stirred at 60°C for 2 hours. The reaction product was poured into water (30 mL) at 0°C. This mixture was extracted with ELISA (2 × 20 mL), washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 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 0.78 (m, 6H), 0.68 (s, 3H). Step 2. To a solution of A36 (800 mg, 2 mmol) in THF (5 mL), 9-BBN (40 mL, 20.0 mmol) at 0°C was added. This mixture was stirred at 25°C for 1 hour. NaOH (13.3 mL, 40 mmol, 3 M) and H2O2 (1.2 mL, 40 mmol) were added at 0°C. This mixture was stirred at 25°C for 2 hours. The reaction product was poured into water. This mixture was extracted with ELISA (2 × 50 mL). The combined organic layers were washed with saturated Na2S2O3 (2 × 50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 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 ( Step 3. To a solution of A37 (500 mg, 1.19 mmol) in DCM (10 mL), TEA (240 mg, 2.38 mmol) and Ac2O (181 mg, 1.78 mmol) were added at 25°C. The reaction mixture was stirred at 25°C for 2 hours. The reaction was quenched with saturated NaHCO3 (10 mL). The mixture was extracted with DCM (2 × 10 mL), washed with brine (2 × 10 mL), dried over Na2SO4, and concentrated to obtain 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 obtain 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), AcCl (17.0 mg, 0.217 mmol) was added at 25°C. This mixture was stirred at 25°C for 2 hours. The reaction product 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 obtain 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 minutes chromatography, 30-90AB_E), C 28 H 49 O2[M+H] + MS ESI calculation value 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), AcCl (12.7 mg, 0.163 mmol) was added at 25°C. This mixture was stirred at 25°C for 2 hours. The reaction product 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 obtain the crude product, which was purified by silica gel column chromatography (PE / Â=20 / 1~8 / 1) to obtain 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 minutes chromatography, 3 0-90AB_E), C 28 H 49 O2[M+H] + MS ESI calculation value 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. Trimethylaluminum (37.2 mL, 2 M in toluene, 74.4 mmol) at 0°C was added dropwise to a solution of BHT (32.6 g, 148 mmol) in toluene (100 mL). The reaction mixture was stirred at 15°C for 1.5 hours. 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 hour. EtMgBr (28.4 mL, 3.0 M in diethyl ether, 74.4 mmol) was added dropwise at -70°C. The reaction mixture was stirred for a further 1 hour at -70°C. This reaction mixture was poured into saturated aqueous critic acid (2 L). The aqueous phase was extracted with phenylethylamine (3 × 1.5 L). The combined organic phases were washed with brine (2 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This was purified by silica gel chromatography using PE:siRNA=10:1 elution to obtain 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 chromatogram) tography, 30-90AB), purity 100%, C 28 H 47 O2[M+H-H2O] + MS ESI calculated 415, found 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 portions. The reaction was stirred at 0°C for 30 minutes. The reaction was quenched with 1M HCl (30 mL) at 0°C and extracted with EtOAc (3×30 mL). The combined organic phases were 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 (400 MHz, 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 387, found 387.

[0235] Example 14. Synthesis of Compounds 34, 35 and 36

Chemical Formula

[0236] Example 16. Synthesis of compounds 37, 37-A, and 37-B [ka] Step 1. DMP (1.04 g, 2.46 mmol) was added at 20°C to a solution of compound 33 (500 mg, 1.23 mmol) in DCM (20 mL). The reaction mixture was stirred at 20°C for 1.5 hours. 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) and brine (50 mL), dried over Na2SO4, filtered, and concentrated to obtain 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, MeMgBr (2.06 mL, 3.0 M, 6.19 mmol) at 0°C was added all at once. After stirring at 20°C for 30 minutes, the mixture was quenched with 50 mL of saturated NH4Cl and extracted with 50 mL of ethyl acetate. The separated organic phase was washed with 100 mL of brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by combiflush (ethyl acetate in PE, 0%-40%) to obtain compound 37 (350 mg, 67%) as an off-white solid. 27 mg was fed. 1 HNMR (400 MHz, 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] + The MS ESI calculated value is 383, and the measured value is also 383. Step 3. Benzoyl chloride (501 mg, 3.57 mmol) was added to a solution of compound 37 (300 mg, 0.716 mmol) in pyridine (10 mL). The reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phase was washed with 1N HCl (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by combiflush (0% to 15% ethyl acetate in PE) to obtain 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) is injected into an SFC (column: AD (250 mm) * Purification was performed using the following conditions: 30 mm, 5 μm; 0.1% NH3, H2O EtOH; gradient 35% B; gradient time (min): 30; flow rate (ml / min): 60). A46 (peak 1,90 mg) was obtained as a white solid, and A47 (peak 2,100 mg) was obtained 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), solutions of MeOH (2 mL) and LiOH.H2O (72 mg, 1.72 mmol) were added at 25°C. This mixture was stirred at 25°C for 17 hours. Water (5 mL) was added. This mixture was extracted with ethyl acetate (2 × 8 mL), washed with brine (2 × 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by flash column (0-30% ethyl acetate in PE, 50 min) to obtain 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 minutes (8 minutes of chromatography, 3 0-90_AB_1.2ml_E), C 28 H 47 [M+H-2H2O]+ MS MS ESI calculated value: 383, measured value: 383 Step 6. To a solution of A47 (100 mg, 0.19 mmol) in THF (5 mL), solutions of MeOH (2 mL) and LiOH.H2O (80 mg, 1.91 mmol) were added at 25°C. This mixture was stirred at 25°C for 17 hours. Water (5 mL) was added. This mixture was extracted with ethyl acetate (2 × 8 mL), washed with brine (2 × 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by flash column (0-30% ethyl acetate in PE, 50 min) to obtain 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 minutes (8 minutes chromatography, 30-90_AB_1.2 ml_E), C 28 H 47 The calculated MS ESI value for [M+H-2H2O]+ is 383, and the measured value is also 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), TMSCF3 (1.76 g, 12.4 mmol) was added under nitrogen at 0°C. This mixture was stirred at 20°C for 1 hour. TBAF (15 mL, 1 M in THF) was added. This mixture was stirred for a further 16 hours at 20°C. This mixture was concentrated to 10 mL under reduced pressure, and DCM (30 mL) was added. This mixture was washed with water (3 × 50 mL) and brine (2 × 50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. This was purified by flash column (0-25% ethyl acetate in PE, 80 min) to obtain compound 38 (400 mg, crude) as an off-white solid. Compound 38 (400 mg, crude) was ground in CH3CN (30 mL) at 80°C to obtain 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-minute chromatography, 30-90AB_E), C 28 H 44 F3O[M-H2O+H] + The MS ESI calculated value is 453, and the measured value is also 453. Step 2. Compound 38 (300 mg) is added to SFC (column: AD (250 mm) * The compounds were purified using a 30mm, 5um filter (conditions: 0.1% NH3H2O ​​IPA, 35% B; flow rate (ml / min): 60) to obtain 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 minutes (2 minutes chromatography, 30-90AB_E), C 28 H 44 F3O[M-H2O+H] + The MS ESI calculated value is 453, and the measured value is also 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-minute chromatography, 30-90AB_E), C 28 H 44 F3O[M-H2O+H] + The MS ESI calculated value is 453, and the measured value is also 453.

[0238] Example 18. Synthesis of Compound 41 [ka] A30 (100 mg, 0.232 mmol) and in THF (10 mL) under N2 To a suspension of Ti(i-PrO)4 (65.9 mg, 0.232 mmol), EtMgBr (0.27 mL, 0.812 mmol) at 20°C was added dropwise. After stirring at 20°C for 1 hour, the mixture was quenched with 0.4 mL of saturated NH4Cl. The mixture was filtered. The filtrate was concentrated. The residue was purified by combiflush (siRNA in PE, 0%-30%) to obtain 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, 30-90 AB), 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, EtMgBr (0.4 mL, 1.21 mmol) at 20°C was added dropwise. After stirring at 20°C for 1 hour, the mixture was quenched with 0.4 mL of saturated NH4Cl. The mixture was filtered. The filtrate was concentrated. The residue was purified by combiflush (ethyl acetate in PE, 0%-30%) to obtain 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 0.343 minutes (2.0 minutes chromatography, 30-90AB), C 29 H 47 [M+H-2H2O] + The MS ESI calculated value is 395, and the measured value is also 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, TMSCF3 (843 mg, 5.93 mmol) was added all at once at 0°C. After stirring at 20°C for 1 hour, TBAF (9.89 mL, 9.89 mmol, 1 M in THF) was added. This mixture was stirred for a further 16 hours at 20°C. This mixture was quenched with 50 mL of saturated NH4Cl and extracted with 50 mL of ethyl acetate. The separated organic phase was washed twice with 100 mL of brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by combiflush (ethyl acetate in PE, 0%~40%) to obtain 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, 30-90 AB), C 28 H 46 F3O[M+H-H2O] + The MS ESI calculated value is 455, and the measured value is also 455. Step 2. Benzoyl chloride (416 mg, 2.96 mmol) was added to a solution of compound 43 (350 mg, 0.740 mmol) in pyridine (10 mL). The reaction mixture was stirred at 50°C for 48 hours. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phase was washed with 1N HCl (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by combiflush (0% to 20% ethyl acetate in PE) to obtain 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) in SFC (column: AD (250 mm) * The mixture was purified using the following conditions: 30 mm, 5 μm; 0.1% NH3H2O ​​MeOH, 40% B; flow rate (ml / min): 60 to obtain A49 (40 mg, 20%) as an oily substance 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 a solution of LiOH•H2O (16.6 mg, 0.69 mmol) in MeOH (1 mL) and H2O (1 mL) at 25°C. The mixture was stirred at 25°C for 17 hours. The mixture was extracted with EtOAc (2×5 mL), washed with brine (2×10 mL), dried over Na2SO4, filtered, purified by flash column chromatography (0-30% EtOAc in PE) to give 43-A (20 mg, impure) as an off-white solid. The product was triturated with CH3CN (2 mL) at 25°C, then the filter cake was dissolved in CH3CN (20 mL) at 80°C. The solution was concentrated under reduced pressure to give 43-A (6 mg, 31%) as an off-white solid. 1 1H NMR (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 = 1.319 min (2 min chromatography, 30-90AB_E), C 28 H 46 F3O[M+H-H2O] + MS ESI calcd. 455, found 455. Step 5. To a solution of A50 (70 mg) in THF (3 mL) was added a solution of LiOH•H2O (50.7 mg, 1.2 mmol) in MeOH (2 mL) and H2O (2 mL) at 25°C. The mixture was stirred at 25°C for 17 hours. The mixture was extracted with EA (2×6 mL), washed with brine (2×10 mL), dried over Na2SO4, filtered, purified by flash column chromatography (0-30% EtOAc in PE, 1 hour) to give 43-B (40 mg, impure) as an oil. The product was recrystallized from 4 mL of CH3CN 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 (2 minutes chromatography, 30-90AB_E), C 28 H 46 F3O[M+H-H2O] + The MS ESI calculated value is 455, and the measured value is also 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 may also be used unless otherwise stated. Optimal reaction conditions may vary depending on the specific reactants or solvent used, but such conditions can be determined by those skilled in the art through conventional optimization.

[0242] Furthermore, as may be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. The selection of suitable protecting groups for specific functional groups, as well as 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 PGMWuts, *Protecting Groups in Organic Synthesis*, 2nd edition, Wiley, New York, 1991, and the references cited therein.

[0243] The compounds provided herein may 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 with respect to the preparation of representative neurostimulant steroids listed herein. The compounds provided herein may be prepared by those skilled in the art of organic synthesis from known or commercially available starting materials and reagents. Exemplary chiral columns available for use in the separation / purification of 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] Reported herein 1 ¹H-NMR (e.g., for the δ (ppm) region from approximately 0.5 to 4 ppm) will be understood as an exemplary interpretation of the compound's NMR spectrum (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 NH3H2O). 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% of B for 1.6 or 2 minutes; Flow rate: 1.8 or 2 mL / min; Column: XBridge C18, 4.6 × 50 mm, 3.5 μm, 45°C NMDA enhancement

[0246] NMDA enhancement was evaluated using whole-cell patch clamps on mammalian cells expressing the NMDA receptor. Whole-cell patch clamp of mammalian cells (Ionworks Barracuda (IWB)) Using the whole-cell patch-clamp method, GlunN1 expressed in mammalian cells was identified. The effects of the compound on the / GluN2A glutamate receptor were investigated. The results are shown in Table 1. HEK293 cells were transformed with adenovirus 5DNA and transfected with cDNA encoding the human GRIN1 / GRIN2A genes. Stable transfectants were selected using the G418 gene and zeosin resistance gene incorporated into the expression plasmid, as well as the selective pressure maintained by G418 and zeosin in the culture medium. Cells were cultured in Dulbecco's Modified Eagle 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 zeosin, 5 μg / ml blastosidine, and 500 μg / ml G418. The effects of the test substance were evaluated using an 8-point concentration-response format (4-well / concentration). All test and control solutions contained 0.3% DMSO and 0.01% Kolliphor® EL (C5135, Sigma). The test substance 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 following this procedure: Electrophysiological procedures: a) Intracellular solution (mM): 50 mM CsCl, 90 mM CsF, 2 mM MgCl2, 5 mM EGTA, 10 mM HEPES. Adjust pH to 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: -70mV, potential during agonist / PAM application: -40mV. Recording procedure: a) Fill the wells of the PPC plate with extracellular buffer (11 μL per well). Add the cell suspension to the wells of the PPC flat electrode using a pipette (9 μL per well). b) Establish whole-cell recording settings by patch perforation and record the membrane current using the built-in patch clamp amplifier. c) Perform two recordings (scans). The first is during pre-application of the test substance only (duration of pre-application, 5 minutes), and the second is with the test substance and agonist (EC). 20 Recordings were made during the simultaneous application of L-glutamate and 30 μM glycine to detect the positive modulatory effect of the test substance. Administration of the test substance: The first pre-application consists of adding 20 μL of 2× concentrated test substance solution at a rate of 10 μL / s (total application time of 2 seconds), and the second consists of adding 20 μL of 1× concentrated test substance and agonist. [Table 1-1] [Table 1-2] In Table 1, "A" indicates a 10-100% enhancement, "B" indicates an enhancement of >100%, and "ND" indicates that measurement was not possible or was not taken. Other Embodiments

[0247] In a claim, an article (e.g., “a,” “an,” and “the”) may mean one or more unless otherwise indicated or evident from the context. Unless otherwise indicated or evident from the context, a claim or description containing “or” between one or more members of a group is considered to satisfy that one, more than one, or all group members are present in, used in, or otherwise related to a given product or process. The present invention includes embodiments in which exactly one member of the group is present in, used in, or otherwise related to a given product or process. The present invention includes embodiments in which more than one or all group members are present in, used in, or otherwise related to a given product or process.

[0248] Furthermore, the present invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims are introduced in another claim. For example, any claim dependent on another claim may be modified to include one or more limitations found in any other claim dependent on the same basic claim. Where elements are presented as a list, for example in the form of a Markush group, each subgroup of that element is also disclosed, and any element may be removed from that group. In general, where the present invention or an aspect of the present invention is referred to as including certain elements and / or features, it should be understood that certain embodiments of the present invention or an aspect of the present invention consist of or essentially consist of such elements and / or features. For the sake of simplicity, those embodiments are not explicitly shown herein in the same language. Not applicable. Note that the terms “comprising” and “containing” are intended to be open and may also allow for the inclusion of further elements or steps. Where a range is given, the endpoint is included. Furthermore, unless otherwise indicated or evident from the context and the understanding of those skilled in the art, values ​​expressed as a range may, unless the context clearly indicates otherwise, assume any particular value or subrange within the range described in the various embodiments of the invention up to one-tenth of the lower limit of that range.

[0249] This application refers to various issued patents, published patent applications, academic articles, and other publications (all of which are incorporated herein by reference). In the event of any conflict between any reference incorporated herein and this specification, this specification shall prevail. Furthermore, any particular embodiment of the Invention that falls within the scope of the Prior Art may be expressly excluded from any one or more of the claims. Such embodiments are considered to be known to those skilled in the art and may be excluded even if such exclusion is not expressly indicated herein. Any particular embodiment of the Invention may be excluded from any claim for any reason, whether or not it relates to the existence of the Prior Art.

[0250] Those skilled in the art will be able to recognize or verify, by mere conventional experimental methods, 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, as is set forth in the appended claims. Those skilled in the art will recognize that various changes and modifications to this description can be made without departing from the spirit or scope of the invention as defined in the following claims.

[0251] In embodiments of the present invention, for example, the following items are provided. (Item 1) Equation (I): [ka] A compound or a pharmaceutically acceptable salt thereof, wherein, R 1 C 1~6 It is alkyl; R 2 and R 3 Each of these independently consists of hydrogen, halogen, and C. 1~6 It is alkyl or carbocyric; or R 2 and R 3 These, together with the carbon atoms to which they are bonded, form a 3- to 8-membered ring; R 6 It either does not exist or is hydrogen; R 7 and R 8 Each of these independently consists of hydrogen, halogen, and C. 1~6 It is alkyl or carbocyric; or R 7 and R 8 Each of them, together with the carbon atoms to which they are bonded, forms a 3- to 8-membered ring; or R 2 and R 7 These, together with the carbon atoms to which they are bonded, form a 3- to 8-membered ring; n is 1, 2, or 3; [ka] represents a single bond or a double bond, where one of them [ka] When it is a double bond, the other is [ka] It is a single bond; [ka] When one of them is a double bond, R 6 It does not exist. A compound or a pharmaceutically acceptable salt thereof. (Item 2) each [ka] However, it is a single bond, as described in item 1. (Item 3) R 1 The compounds listed in item 1, which are methyl (e.g., -CHF2, -CF3, -CH2OCH3 or -CH2OCH2CH3), ethyl, or isopropyl. (Item 4) R 1 The compounds listed in item 3, which are methyl or ethyl. (Item 5) R 2 and R 3 Each of them independently produces hydrogen and C 1~6 It is alkyl or carbocyric, or R 2 and R 3 These are compounds described in item 1, which, together with the carbon atoms to which they are bonded, form a 3- to 8-membered ring. (Item 6) The compound described in item 5, wherein the 3- to 8-membered ring is a carbocyclyl ring (e.g., cyclopropyl). (Item 7) R 2 and R 3 Each of them independently produces hydrogen and C 1~6 A compound as described in item 5, which is alkyl or carbocyacrylic. (Item 8) R 2 and R 3The compounds described in item 7, each of which is independently hydrogen, methyl (e.g., -CH3, -CF3), ethyl (e.g., -CH2CH3, -CH2CF3), propyl, isopropyl, cyclopropyl, or butyl. (Item 9) R 2 However, it is hydrogen, methyl (e.g., -CH3, -CF3) or ethyl, as described in item 7. The compound listed. (Item 10) R 3 The compounds listed in item 7, which are methyl (e.g., -CH3, -CF3), ethyl (e.g., -CH2CH3, CH2CF3), propyl, isopropyl, cyclopropyl, or butyl. (Item 11) R 2 However, it is hydrogen, and R 3 However, C 1~6 A compound that is alkyl, as described in item 7. (Item 12) R 2 However, C 1~6 It is alkyl, R 3 However, C 1~6 A compound that is alkyl, as described in item 7. (Item 13) [ka] The compounds listed in item 1, each of which is a single bond. (Item 14) R 7 and R 8 However, it is hydrogen, as described in item 1. (Item 15) The compound listed in item 1, where n is 1. (Item 16) n is 1, R 7 and R 8 However, it is hydrogen, as described in item 1. (Item 17) The compound of formula (I) is, formula (II): [ka] A compound of the compound described in item 1 or a pharmaceutically acceptable salt thereof. (Item 18) The compound of formula (I) is either of formula (II-A) or formula (II-B): [ka] A compound of the compound described in item 17 or a pharmaceutically acceptable salt thereof. (Item 19) The compound of formula (I) is also known as formula (II-Bi) or formula (II-B-ii): [ka] A compound of the compound described in item 17 or a pharmaceutically acceptable salt thereof. (Item 20) The compound of formula (I) is of formula (II-B-iii): [ka] A compound of the compound described in item 17 or a pharmaceutically acceptable salt thereof. (Item 21) The compound of formula (I) is, formula (III): [ka] A compound of the compound described in item 1 or a pharmaceutically acceptable salt thereof. (Item 22) The compound of formula (III) is either of formula (III-A) or (III-B): [ka] A compound of the compound described in item 21 or a pharmaceutically acceptable salt thereof. (Item 23) The compound of formula (III-B) is either of formula (III-C) or (III-D): [ka] A compound of the compound described in item 21 or a pharmaceutically acceptable salt thereof. (Item 24) The compound of formula (III-A) is either of formula (III-E) or (III-F): [ka] A compound of the compound described in item 21 or a pharmaceutically acceptable salt thereof. (Item 25) The compound of formula (III) is either formula (III-Aia) or formula (III-Bia): [ka] A compound of the compound described in item 21 or a pharmaceutically acceptable salt thereof. (Item 26) R 1 The compounds listed in item 25, which are methyl (e.g., -CHF2, -CF3, -CH2OCH3 or -CH2OCH2CH3), ethyl, or isopropyl. (Item 27) R 2 and R 3 Each of them independently produces hydrogen and C 1~6 It is alkyl or carbocyric, or R 2 and R 3 However, these compounds, as described in item 21, form a 3- to 8-membered ring together with the carbon atoms to which they are bonded. (Item 28) R 2 and R 3Each of them independently produces hydrogen and C 1~6 A compound as described in item 27, which is alkyl or carbocyacrylic. (Item 29) R 2 and R 3 Each of these independently produces hydrogen, methyl (e.g., -CH3, -CF3), and ether. The compounds listed in item 28, which are thiol (e.g., -CH2CH3, -CH2CF3), propyl, isopropyl, cyclopropyl, or butyl. (Item 30) R 2 The compounds listed in item 29, wherein the compound is hydrogen, methyl (e.g., -CH3, -CF3), or ethyl. (Item 31) R 3 The compounds described in item 27, which are methyl (e.g., -CH3, -CF3), ethyl (e.g., -CH2CH3, -CH2CF3), propyl, isopropyl, cyclopropyl, or butyl. (Item 32) The aforementioned compound, [ka] A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following. (Item 33) The compound of formula (I) is, formula (IV): [ka] A compound of the compound described in item 1 or a pharmaceutically acceptable salt thereof. (Item 34) R 1 The compounds listed in item 33, which are methyl (e.g., -CHF2, -CF3, -CH2OCH3 or -CH2OCH2CH3), ethyl, or isopropyl. (Item 35) R 2 and R 3 Each of them independently produces hydrogen and C 1~6It is alkyl or carbocyric, or R 2 and R 3 However, these compounds, as described in item 33, form a 3- to 8-membered ring together with the carbon atoms to which they are bonded. (Item 36) R 2 and R 3 Each of them independently produces hydrogen and C 1~6 A compound as described in item 35, which is alkyl or carbocyric. (Item 37) R 2 and R 3 The compounds described in item 36, each of which is independently hydrogen, methyl (e.g., -CH3, -CF3), ethyl (e.g., -CH2CH3, CH2CF3), propyl, isopropyl, cyclopropyl, or butyl. (Item 38) R 2 However, it is hydrogen, methyl (e.g., -CH3, -CF3) or ethyl, see item 37. The compound described. (Item 39) R 3 The compounds listed in item 36 are methyl (e.g., -CH3, -CF3), ethyl (e.g., -CH2CH3, -CH2CF3), propyl, isopropyl, cyclopropyl, and butyl. (Item 40) The aforementioned compound, [ka] The compound described in item 33 or a pharmaceutically acceptable salt thereof. (Item 41) The compound of formula (I) is, formula (V): [ka] A compound of the compound described in item 1 or a pharmaceutically acceptable salt thereof. (Item 42) The compound of formula (I) is, formula (VA): [ka] A compound of the compound described in item 17 or a pharmaceutically acceptable salt thereof. (Item 43) The compound of formula (I) is, formula (VB): [ka] A compound of the compound described in item 1 or a pharmaceutically acceptable salt thereof. (Item 44) The compound of formula (III) is either of formula (VC) or formula (VD): [ka] A compound of the compound described in item 21 or a pharmaceutically acceptable salt thereof. (Item 45) The compound of formula (I) is given by formula (VEi): [ka] A compound of the compound described in item 1 or a pharmaceutically acceptable salt thereof. (Item 46) The compound of formula (I) is also formula (VE-ii) or (VE-iii): [ka] A compound of the compound described in item 1 or a pharmaceutically acceptable salt thereof. (Item 47) The aforementioned compound, [ka] [ka] [ka] [ka] A compound listed in item 1 or a pharmaceutically acceptable salt thereof, selected from the above. (Item 48) A pharmaceutical composition comprising the compound described in item 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. (Item 49) A method for inducing sedation or anesthesia, comprising administering an effective amount of the compound described in item 1 or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition thereof to a subject. (Item 50) A method for treating or preventing any of the disorders described herein, comprising the step of administering an effective amount of the compound described in item 1 or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition thereof to a subject in need of such treatment or prevention. (Item 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), a structural disorder affecting the GI, anal disorders (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas), colon polyps, cancer, or colitis. (Item 52) The method according to item 50, wherein the disorder is inflammatory bowel disease. (Item 53) The method according to item 50, wherein the disorder is cancer, diabetes, or sterol synthesis disorder. (Item 54) The method according to item 50, wherein the disorder is a metabolic disorder. (Item 55) A method for treating or preventing CNS-related symptoms, comprising the step of administering an effective amount of the compound described in item 1 or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition thereof to a subject in need of such treatment or prevention. (Item 56) The aforementioned CNS-related symptoms include adjustment disorder, anxiety disorders (obsessive-compulsive disorder, post-traumatic stress disorder, etc.) (including social phobia), cognitive impairment (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, and suicidal ideation), schizophrenia or other psychotic disorders (including schizoaffective disorder), sleep disorders (including insomnia), substance-related disorders, personality disorders (including obsessive-compulsive personality disorder), and autism spectrum disorders (including those with mutations in Shank group proteins (e.g., Shank3)). The method described in item 55, which includes neurodevelopmental disorders (including Rett syndrome and tuberous sclerosis syndrome), multiple sclerosis, sterol synthesis disorders, pain (including acute and chronic pain), encephalopathy secondary to a medical condition (including hepatic encephalopathy and anti-NMDA receptor encephalitis), paroxysmal disorders (including status epilepticus and monogenotype epilepsy, e.g., Dravet disease), stroke, traumatic brain injury, motor disorders (including Huntington's disease and Parkinson's disease), visual impairment, hearing loss and tinnitus. (Item 57) The method according to item 55, wherein the impairment is a sterol synthesis disorder.

Claims

1. Formula (III): 【Chemistry 1】 A compound or a pharmaceutically acceptable salt thereof, wherein, R1 is a substituted or unsubstituted C1-6 alkyl group; Each of R2 and R3 is independently hydrogen, a halogen, a substituted or unsubstituted C1-6 alkyl, or a substituted or unsubstituted carbocyclyl; or R2 and R3, together with the carbon atoms to which they are bonded, form substituted or unsubstituted 3- to 8-membered rings; and R6 is hydrogen. A compound or a pharmaceutically acceptable salt thereof.

2. The compound of formula (III) is of formula (III-A) or formula (III-B): 【Chemistry 2】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. The compound of formula (III-B) is of formula (III-C) or formula (III-D): 【Transformation 3】 A compound of the compound described in claim 2 or a pharmaceutically acceptable salt thereof.

4. The compound of formula (III-A) is of formula (III-E) or formula (III-F): 【Chemistry 4】 A compound of the compound described in claim 2 or a pharmaceutically acceptable salt thereof.

5. The compound of formula (III) is of formula (III-A-i-a) or formula (III-B-i-a): 【Transformation 5】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof.

6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein R1 is methyl, ethyl, or isopropyl.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein R1 is methyl or ethyl.

8. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein each of R2 and R3 is independently hydrogen, a substituted or unsubstituted C1-6 alkyl group, or a substituted or unsubstituted carbocyclyl group; or R2 and R3, together with the carbon atoms to which they are bonded, form a substituted or unsubstituted 3-8 membered ring.

9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein the substituted or unsubstituted 3- to 8-membered ring is a substituted or unsubstituted carbocyclyl ring.

10. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein each of R2 and R3 is independently hydrogen, a substituted or unsubstituted C1-6 alkyl group, or a substituted or unsubstituted carbocyclyl group.

11. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein each of R2 and R3 is independently hydrogen, -CH3, -CF3, -CH2CH3, -CH2CF3, propyl, isopropyl, cyclopropyl, or butyl.

12. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen, -CH3, -CF3, or -CH2CH3.

13. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein R3 is -CH3, -CF3, -CH2CH3, -CH2CF3, propyl, isopropyl, cyclopropyl, or butyl.

14. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen and R3 is a substituted or unsubstituted C1-6 alkyl group.

15. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein R2 is a substituted or unsubstituted C1-6 alkyl group and R3 is a substituted or unsubstituted C1-6 alkyl group.

16. The compound of formula (III-A-i-a) or formula (III-B-i-a) is 【Chemistry 16】 A compound according to claim 5 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

17. The compound is 【Chemistry 17-1】 【Chemistry 17-2】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the compound or a pharmaceutically acceptable salt thereof.

18. The compound is 【Chemistry 18-1】 【Chemistry 18-2】 A compound according to claim 17, selected from the group consisting of the following.

19. The compound is as follows: 【Chemistry 19】 The compound according to claim 18.

20. The compound is as follows: 【Chemistry 20】 The compound according to claim 18.

21. The compound is as follows: 【Chemistry 21】 The compound according to claim 18.

22. The compound is as follows: 【Chemistry 22-1】 【Chemistry 22-2】 and 【Chemistry 22-3】 A pharmaceutically acceptable salt of the compound according to claim 17, selected from the group consisting of the following.

23. The compound is as follows: 【Chemistry 23】 A pharmaceutically acceptable salt of the compound according to claim 22.

24. The compound is as follows: 【Chemistry 24】 A pharmaceutically acceptable salt of the compound according to claim 22.

25. The compound is as follows: 【Chemistry 25】 A pharmaceutically acceptable salt of the compound according to claim 22.

26. A pharmaceutical composition comprising the compound according to any one of claims 1 to 21 and a pharmaceutically acceptable carrier.

27. ​​A pharmaceutical composition comprising a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier according to any one of claims 1 to 17 and 22 to 25.

28. A pharmaceutical composition for inducing sedation or anesthesia, comprising a compound or a pharmaceutically acceptable salt according to any one of claims 1 to 25.

29. A pharmaceutical composition for treating a disorder, comprising a compound or pharmaceutically acceptable salt according to any one of claims 1 to 25, wherein the disorder is a gastrointestinal (GI) disorder, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), structural disorders affecting the GI duct, anal disorders, colon polyps, cancer, diabetes mellitus, sterol synthesis disorders, metabolic disorders, or colitis.

30. A pharmaceutical composition for preventing a disorder, comprising a compound or pharmaceutically acceptable salt according to any one of claims 1 to 25, wherein the disorder is a gastrointestinal (GI) disorder, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), structural disorders affecting the GI duct, anal disorders, colon polyps, cancer, diabetes mellitus, sterol synthesis disorders, metabolic disorders, or colitis.

31. The pharmaceutical composition according to claim 29 or 30, wherein the disorder is inflammatory bowel disease.

32. The pharmaceutical composition according to claim 29 or 30, wherein the disorder is cancer, diabetes, or sterol synthesis disorder.

33. The pharmaceutical composition according to claim 29 or 30, wherein the disorder is a metabolic disorder.

34. A pharmaceutical composition for treating a disorder, comprising a compound or a pharmaceutically acceptable salt according to any one of claims 1 to 25, wherein the disorder is a disorder associated with Smith-Lemle-Oppitz syndrome, desmosterosis, sitosterolemia, cerebral tendon xanthomatosis, mevalonate kinase deficiency, SC4MOL gene mutation, Niemann-Pick disease, autism spectrum disorder, or phenylketonuria.

35. A pharmaceutical composition for preventing a disorder, comprising a compound or a pharmaceutically acceptable salt according to any one of claims 1 to 25, wherein the disorder is a disorder associated with Smith-Lemle-Oppitz syndrome, desmosterosis, sitosterolemia, cerebral tendon xanthomatosis, mevalonate kinase deficiency, SC4MOL gene mutation, Niemann-Pick disease, autism spectrum disorder, or phenylketonuria.

36. A pharmaceutical composition for treating CNS-related symptoms, comprising a compound or a pharmaceutically acceptable salt according to any one of claims 1 to 25.

37. A pharmaceutical composition for preventing CNS-related symptoms, comprising a compound or a pharmaceutically acceptable salt described in any one of claims 1 to 25.

38. The pharmaceutical composition according to claim 36 or 37, wherein the CNS-related symptoms are adjustment disorder, anxiety disorder, cognitive impairment, dissociative disorder, eating disorder, mood disorder, psychotic disorder, sleep disorder, substance-related disorder, personality disorder, autism spectrum disorder, neurodevelopmental disorder, multiple sclerosis, sterol synthesis disorder, pain, encephalopathy secondary to a certain condition, paroxysmal disorder, stroke, traumatic brain injury, motor disorder, visual impairment, hearing loss, or tinnitus.

39. The pharmaceutical composition according to claim 38, wherein the CNS-related symptoms are sterol synthesis disorders.

40. The pharmaceutical composition according to claim 38, wherein the CNS-related symptoms are a psychotic disorder, and the psychotic disorder is schizophrenia.

41. The pharmaceutical composition according to claim 38, wherein the CNS-related symptoms are autism spectrum disorder.

42. The pharmaceutical composition according to claim 38, wherein the CNS-related symptom is a motor disorder, and the motor disorder is Huntington's disease or Parkinson's disease.

43. The pharmaceutical composition according to claim 38, wherein the CNS-related symptoms are cognitive impairment, and the cognitive impairment is Alzheimer's disease.

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