Oxysterols and methods of use thereof

Abstract

To provide new oxysterols that modulate an NMDA receptor for the prevention and treatment of conditions associated with the NMDA expression and function.SOLUTION: The invention provides compounds according to formula (I), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Priority claims This application claims priority to U.S. Application No. 62 / 317,002, filed April 1, 2016, the entire contents of which are incorporated herein by reference. [Background technology]

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

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

[0004] Summary of the Invention Provided herein are novel oxysterols useful for preventing and / or treating a wide range of disorders, including, but not limited to, NMDA-mediated disorders. Additionally, provided are pharmaceutical compositions containing the compounds of the invention, as well as methods of their use and treatment. In one aspect, the compound of formula (IA): [ka] or a pharmaceutically acceptable salt thereof, wherein in formula (IA): A is carbocyclyl or heterocyclyl (e.g., unsubstituted or substituted carbocyclyl or heterocyclyl, e.g., heterocyclyl substituted with at least one heteroatom (e.g., 1, 2, or 3 heteroatoms)); R 1 is C 1~6 alkyl (e.g., -CH3 or -CH2CH3); R 5 is absent or hydrogen; [ka] represents a single or double bond, where one [ka] is a double bond, the other [ka] is a single bond, and R 5 does not exist. In one aspect, the compound of formula (IB): [ka] or a pharmaceutically acceptable salt thereof, wherein in formula (IB): 1 is hydrogen or C 1~6 alkyl (e.g., -CH3 or -CH2CH3); R 5 is absent or hydrogen; Z is —C(R A )2-, -NR B -, -O-, or -S-; X is a halogen, C 1~6 Alkyl, or -OR C and;R A is hydrogen, halogen, or C 1~6 alkyl; R B is hydrogen, C 1~6 Alkyl, -C(O)R C , -C(O)OR C , -C(O)N(R D )2, or -S(O)2R C and;R C is hydrogen or C 1~6 alkyl; each R D are independently hydrogen, C 1~6 m is an integer selected from 1, 2, and 3; n is an integer selected from 1, 2, and 3; p is an integer selected from 0, 1, 2, 3, 4, and 5; and [ka] represents a single or double bond, where one [ka] is a double bond, the other [ka] is a single bond, and R 5 does not exist. In some embodiments, the compound has Formula (II-A), Formula (II-B), or Formula (II-C): [ka] is a compound of In some embodiments, p is an integer selected from 0, 1, or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 1 and X is a halogen. In some embodiments, the compound has formula (II-D), formula (II-E), or formula (II-F): [ka] [ka] is a compound of In some embodiments, the compound has formula (II-G) or formula (II-H): [ka] is a compound of In some embodiments, the compound has formula (II-I) or formula (II-J): [ka] is a compound of In some embodiments, R 1 is C 1~6 In some embodiments, R 1 is methyl or ethyl. In some embodiments, R 1 are -CH3, -CF3, and -CH2CH3. In some embodiments, Z is —C(R A )2-, -O-, or -NR BAlternatively, Z is -CH2-. Alternatively, Z is O. Alternatively, Z is -NR B - where R B is -NH-, -N-(C1-C4 alkyl)-, or -NC(O)-(C1-C4 alkyl). In some embodiments, R A is halogen (e.g., —F). In some embodiments, Z is —CH 2 —, —CF 2 —, or —C(CH 3 ) 2 —. In some embodiments, the compound is: [ka] is. In some embodiments, the compound is: [ka] is. In some embodiments, Z is —O— or —NR B -It is. In some embodiments, the compound is: [ka] is. In some embodiments, the compound is: [ka] is. In some embodiments, the compound is: [ka] is. In some embodiments, Z is -NH-, -NMe-, or -NAc-. In some embodiments, the compound is: [ka] is. In some embodiments, Z is -CH2-. In some embodiments, Z is -C(CH3)2-. In some embodiments, Z is -CF2-. In some embodiments, m is 1, n is 2, and Z is -O-. In some embodiments, m is 2, and n is 2. In some embodiments, m is 3, and n is 1. In some embodiments, m is 3, n is 1, and Z is -O-. In some embodiments, m is 2, n is 2, and Z is -O- or -NR B -It is. In some embodiments, the compound is: [ka] [ka] [ka] is. In some embodiments, the compound is: [ka] [ka] [ka] is a pharmaceutically acceptable salt of

[0005] In one aspect, provided herein is a pharmaceutical composition comprising a compound as described herein (e.g., of Formula (IA), (IB), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In another aspect, provided herein is a method of inducing sedation or anesthesia, the method comprising administering to a subject an effective amount of a compound as described herein (e.g., a compound of Formula (IA), (IB), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0006] In one aspect, provided herein is a method for treating or preventing a disorder described herein, the method comprising administering to a subject in need thereof an effective amount of a compound as described herein (e.g., a compound of Formula (IA), (IB), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0007] In some embodiments, the disorder is a gastrointestinal (GI) disorder, such as constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) (e.g., ulcerative colitis, Crohn's disease), structural disorders affecting the GI, anal disorders (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas), colon polyps, cancer, colitis.

[0008] In some embodiments, the disorder is inflammatory bowel disease.

[0009] In some embodiments, the disorder is cancer, diabetes, or a sterol synthesis disorder.

[0010] In some embodiments, the disorder is a metabolic disorder.

[0011] In one aspect, provided herein is a method for treating or preventing a CNS-related condition, the method comprising administering to a subject in need thereof an effective amount of a compound as described herein (e.g., a compound of Formula (IA), (IB), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0012] In some embodiments, the CNS-related condition is an adjustment disorder, an anxiety disorder (including obsessive-compulsive disorder, post-traumatic stress disorder, and social phobia), a cognitive disorder (including Alzheimer's disease and other forms of dementia), a dissociative disorder, an eating disorder, a mood disorder (including depression (e.g., postpartum depression), bipolar disorder, dysthymic disorder, suicidality), schizophrenia or other psychotic disorders (including schizoaffective psychosis), a sleep disorder (including insomnia), a substance-related disorder, a personality disorder (including obsessive-compulsive personality disorder), an autism spectrum disorder (including those containing mutations in the Shank family of proteins (e.g., Shank3)), a neurodevelopmental disorder (including Rett syndrome, tuberous sclerosis complex), multiple sclerosis, a sterol synthesis disorder, pain (including acute pain and chronic pain), a brain disorder secondary to a medical condition (including hepatic encephalopathy and anti-NMDA receptor encephalitis), a seizure disorder, or These include: epilepsy disorders (including status epilepticus and monogenic forms of epilepsy, such as Dravet's disease), stroke, traumatic brain injury, movement disorders (including Huntington's disease and Parkinson's disease), visual impairment, hearing impairment, and tinnitus.

[0013] In some embodiments, the disorder is a sterol synthesis disorder.

[0014] In one aspect, provided herein is a method for treating or preventing an autism disorder associated with Smith-Lemli-Opitz syndrome (SLOS), desmosterolosis, sitosterolemia, cerebrotendinous xanthomatosis (CTX), mevalonate kinase deficiency syndrome (MKD), SC4MOL gene mutations (SMO deficiency), Niemann-Pick disease, or phenylketonuria, the method comprising administering to a subject in need thereof an effective amount of a compound as described herein (e.g., a compound of Formula (IA), (IB), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0015] In some embodiments, the disorder is cancer, diabetes, or a sterol synthesis disorder.

[0016] In one aspect, provided herein is a method for treating or preventing a CNS-related condition, the method comprising administering to a subject in need thereof an effective amount of a compound described herein (e.g., a compound of Formula (IA), (IB), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the CNS-related condition is an adjustment disorder, an anxiety disorder (including obsessive-compulsive disorder, post-traumatic stress disorder, and social phobia), a cognitive disorder (including Alzheimer's disease and other forms of dementia), a dissociative disorder, an eating disorder, a mood disorder (including depression (e.g., postpartum depression), bipolar disorder, dysthymic disorder, suicidality, schizophrenia or other psychotic disorders (including schizoaffective psychosis), a sleep disorder (including insomnia), a substance-related disorder, a personality disorder (including obsessive-compulsive personality disorder), an autism spectrum disorder (including Shank group proteins (e.g., These disorders include those containing mutations to Shank3), neurodevelopmental disorders (including Rett syndrome and tuberous sclerosis complex), multiple sclerosis, disorders of sterol synthesis, pain (including acute and chronic pain), brain disorders secondary to certain medical conditions (including hepatic encephalopathy and anti-NMDA receptor encephalitis), seizure disorders (including status epilepticus and monogenic forms of epilepsy, such as Dravet's disease), stroke, traumatic brain injury, movement disorders (including Huntington's disease and Parkinson's disease), visual impairment, hearing impairment, and tinnitus. definition chemical definition

[0017] The definitions of specific functional groups and chemical terms are explained in detail below.Chemical elements are identified according to the Periodic Table of Elements (CAS version, Handbook of Chemistry and Physics, 75th edition, inside cover), and specific functional groups are generally defined as described therein.In addition, the general rules of organic chemistry and specific functional moieties 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 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.

[0018] The compounds described herein may contain one or more asymmetric centers and therefore may exist as various isomers, e.g., enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC), supercritical fluid chromatography (SFC), and chiral salt formation and crystallization; or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wil See, e.g., E.L. Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, ed., University of Notre Dame Press, Notre Dame, IN 1972). The present invention further includes the compounds described herein as individual isomers substantially free of other isomers, and alternatively as mixtures of various isomers.

[0019] In one embodiment, the stereoisomers described herein are enriched in the stereoisomeric form depicted for the compound. For example, the stereoisomers can have an enantiomeric or diastereomeric excess of at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%.

[0020] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1~6 "Alkyl" 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 is intended to encompass alkyl of the formula:

[0021] The following terms are intended to have the meanings provided below and are useful in understanding the specification and the intended scope of the invention. When describing the present invention, which may include compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms, when present, have the following meanings, unless otherwise indicated. As described herein, it should also be understood that any of the moieties defined below can be substituted with various substituents, and that each definition is intended to encompass substituted moieties within their scope as described below. Unless otherwise stated, the term "substituted" is defined as described below. It should further be understood that the terms "group" and "radical" can be considered interchangeable when used herein. The articles "a" and "an" can be used herein to refer to one or more (i.e., at least one) of the grammatical object of the article. By way of example, "an analogue" means one analog or more analogs.

[0022] "Aliphatic" refers to an alkyl group, alkenyl group, alkynyl group, or carbocyclyl group, as defined herein.

[0023] "Alkyl" means the radical of a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1~20 In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C 1~12 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1~10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1~9 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1~8 In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C1~7 In some embodiments, an alkyl group has 1 to 6 carbon atoms (also referred to herein as "lower alkyl" or "C 1~6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1~5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1~4 In some embodiments, In the formula, the alkyl group has 1 to 3 carbon atoms ("C 1~3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1~2 In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2~6 alkyl). C 1~6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each occurrence of an alkyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents; for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1~10 In certain embodiments, the alkyl group is a substituted C 1~10Common abbreviations for alkyl include Me(-CH), Et(-CHCH), iPr(-CH(CH)), nPr(-CHCHCH), n-Bu(-CHCHCHCHCH), or i-Bu(-CHCH(CH)).

[0024] "Alkylene" refers to an alkyl group in which two hydrogens are removed to provide a divalent radical, and which may be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), butylene (-CHCHCHCHCH-), pentylene (-CHCHCHCHCHCH-), and hexylene (-CHCHCHCHCHCHCH-). Exemplary substituted alkylene groups (e.g., 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-), and substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-). Examples of alkylene groups include, but are not limited to, -(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-, and the like. When a range or number of carbons is provided for a particular alkylene group, it is understood that the range or number refers to the range or number of carbons in a linear divalent chain of carbons. An alkylene group can be substituted or unsubstituted with one or more substituents as described herein.

[0025] "Alkenyl" refers to the radical of a straight- or branched-chain hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and, optionally, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) ("C 2~20In certain embodiments, an alkenyl group does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C 2~10 In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2~5 alkenyl"). In some embodiments, The alkenyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, an alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., 2-butenyl) or terminal (e.g., 1-butenyl). C 2~4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each occurrence of an alkenyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2~10 In certain embodiments, the alkenyl group is a substituted C 2~10 It is alkenyl.

[0026] "Alkynyl" refers to the radical of a straight- or branched-chain hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) ("C 2~20 In certain embodiments, alkynyl groups contain no double bonds. In some embodiments, alkynyl groups have 2 to 10 carbon atoms ("C 2~10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2~4In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (e.g., 2-butynyl) or terminal (e.g., 1-butynyl). C 2~4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 Alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Further examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each occurrence of an alkynyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents; for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2~10 In certain embodiments, the alkynyl group is a substituted C 2~10 It is alkynyl.

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

[0028] "Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement) in which 6 to 14 ring carbon atoms and 0 heteroatoms are provided in the aromatic ring system ("C 6~14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl"; e.g., 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 to one or more carbocyclyl or heterocyclyl groups, where the bonding radical or point of attachment is on the aryl ring, and in such cases the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. In particular, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each occurrence of an aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl"), or is substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6~14 In certain embodiments, the aryl group is a substituted C 6~14 It is aryl.

[0029] 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.

[0030] Representative examples of substituted aryl include: [ka] where R 56 and R 57 can be hydrogen, and R 56 and R 57 At least one of the following is independently selected from C1-C8 alkyl, C1-C8 haloalkyl, 4- to 10-membered heterocyclyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 , N.R. 58 SOR 59 , N.R. 58 SO2R 59 , COO alkyl, COO aryl, CONR 58 R 59 ,CONR 58 OR 59 , N.R. 58 R 59 , SO2NR 58 R 59 , S-alkyl, SO alkyl, SO alkyl, S aryl, SO aryl, SO aryl; or R 56 and R 57 may be linked to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms (optionally containing one or more heteroatoms selected from the group N, O, or S). 60 and R 61are independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, substituted C6-C 10 It is aryl, 5- to 10-membered heteroaryl or substituted 5- to 10-membered heteroaryl.

[0031] "Fused aryl" refers to an aryl having two of its ring carbons in common with a second aryl or heteroaryl ring, or with a carbocyclyl or heterocyclyl ring.

[0032] "Aralkyl" is a subset of alkyl and aryl, as defined herein, and refers to an optionally substituted alkyl group substituted with an optionally substituted aryl group.

[0033] "Heteroaryl" refers to a radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π-electrons shared in a cyclic arrangement) in which ring carbon atoms and 1 to 4 ring heteroatoms are provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, if valence allows. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, where the point of attachment is on the heteroaryl ring; in such cases, the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, where the point of attachment is on either the aryl ring or the heteroaryl ring, and in such cases the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., iridium) are also included. Indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on the ring with a heteroatom (e.g., 2-indolyl) or on the ring without a heteroatom (e.g., 5-indolyl).

[0034] In some embodiments, heteroaryl groups are 5- to 10-membered aromatic ring systems having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, heteroaryl groups are 5- to 8-membered aromatic ring systems having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In some embodiments, heteroaryl groups are 5- to 6-membered aromatic ring systems having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heteroaryl"). In some embodiments, 5- to 6-membered heteroaryls have 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each occurrence of a heteroaryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, a heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, a heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0035] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0036] Representative examples of heteroaryls include: [ka] where each Z is a carbonyl, N, NR65 , O and S; R 65 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5- to 10-membered heteroaryl.

[0037] "Heteroaralkyl" is a subset of alkyl and heteroaryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted heteroaryl group.

[0038] "Carbocyclyl" or "carbocyclic" means a ring system having 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10 carbocyclyl). Exemplary C 3~6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. 3~8 The carbocyclyl group includes the above-mentioned C 3~6Examples include, but are not limited to, carbocyclyl groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. 3~10 The carbocyclyl group includes the above-mentioned C 3~8 Carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like. When the foregoing examples are illustrated, in certain embodiments, a carbocyclyl group is monocyclic ("monocyclic carbocyclyl") or contains a fused, bridged, or spiro ring system (e.g., a bicyclic system ("bicyclic carbocyclyl")), which may be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, where the point of attachment is on the carbocyclyl ring, and in such cases the number of carbons continues to refer to the number of carbons in the carbocyclyl ring system. Unless otherwise specified, each occurrence of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted"). In certain embodiments, a carbocyclyl group is an unsubstituted C 3~10 In certain embodiments, the carbocyclyl group is a substituted C 3~10 It is a carbocyclyl.

[0039] In some embodiments, "carbocyclyl" refers to a monocyclic saturated carbocyclyl group having 3 to 10 ring carbon atoms ("C 3~10In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5~6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5~10 Cycloalkyl). C 5~6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3~6 Examples of cycloalkyl groups include the above-mentioned C 5~6 Cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4). 3~8 Examples of cycloalkyl groups include the above-mentioned C 3~6 Cycloalkyl groups include cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each occurrence of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C 3~10 In certain embodiments, the cycloalkyl group is a substituted C 3~10 It is cycloalkyl.

[0040] "Heterocyclyl" or "heterocyclic" refers to the radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon or nitrogen atom, when valence allows. Heterocyclyl groups can be monocyclic ring systems ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems (e.g., bicyclic systems ("bicyclic heterocyclyl")), and can be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups, where the point of attachment is on the carbocyclyl or heterocyclyl ring, or on a ring system in which a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the heterocyclyl ring; in such cases, the number of ring members continues to refer to the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each occurrence of heterocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0041] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (a "5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heterocyclyl"). A 5- to 6-membered non-aromatic ring system having heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heterocyclyl"). In some embodiments, a 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0042] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclic rings) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclic rings) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0043] A "nitrogen-containing heterocyclyl" group refers to a 4- to 7-membered non-aromatic ring group containing at least one nitrogen atom, including, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazines (e.g., N-methylpiperazine). Specific examples include azetidine, piperidone, and piperazone.

[0044] "Hetero," when used to describe a compound or a group present on a compound, means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero can apply to any of the hydrocarbyl groups described above having 1 to 5, particularly 1 to 3, heteroatoms (e.g., alkyl, e.g., heteroalkyl; cycloalkyl, e.g., heterocyclyl; aryl, e.g., heteroaryl; cycloalkenyl, e.g., cycloheteroalkenyl, etc.).

[0045] "Acyl" means -C(O)R 20 radical, where R 20 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein. "Alkanoyl" refers to a group in which R 20is an acyl group where the aryl group is a group other than hydrogen. Representative acyl groups include formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), --C(O)-C1-C8 alkyl, and -C(O)-(CH2). t (C6-C 10 aryl), -C(O)-(CH2) t (5-10 membered heteroaryl), -C(O)-(CH2) t (C3-C 10 cycloalkyl) and -C(O)-(CH2) t (4- to 10-membered heterocyclyl) (t is an integer from 0 to 4). 21 is C1-C8 alkyl substituted with halo or hydroxy; or C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl (each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy).

[0046] "Alkoxy" means -OR 29 group, where R 29 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e., having 1 to 6 carbon atoms. Further particular alkoxy groups have 1 to 4 carbon atoms.

[0047] In certain embodiments, R 29 is amino, substituted amino, C6-C 10 Aryl, aryloxy, carboxyl, cyano, C3-C 10 The "substituted alkoxy" group is a group having one or more substituents selected from the group consisting of cycloalkyl, 4- to 10-membered heterocyclyl, halogen, 5- to 10-membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2-, and aryl-S(O)2-, for example, 1 to 5 substituents, particularly 1 to 3 substituents, and particularly 1 substituent. Exemplary "substituted alkoxy" groups include -O-(CH2) t (C6~C 10 aryl), -O-(CH2) t (5-10 membered heteroaryl), -O-(CH2) t (C3~C 10 cycloalkyl) and -O-(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present can itself be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. Particularly exemplary "substituted alkoxy" groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2.

[0048] "Amino" refers to the -NH2 radical.

[0049] "Substituted amino" refers to a group of the formula -N(R 38 )2, where R 38 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted a alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino protecting group, wherein R 38 At least one of R is not hydrogen. 38 are independently hydrogen, C1-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl or C3-C 10 cycloalkyl; or C1-C8 alkyl substituted with halo or hydroxy; C3-C8 alkenyl substituted with halo or hydroxy; C3-C8 alkynyl substituted with halo or hydroxy, or -(CH2) t (C6~C 10 aryl), -(CH2) t (5-10 membered heteroaryl), -(CH2) t (C3~C 10 cycloalkyl) or -(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 8, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; or both R 38 The groups are linked to form an alkylene group.

[0050] Exemplary "substituted amino" groups include -NR 39 -C1-C8 alkyl, -NR 39 -(CH2) t (C6~C 10 aryl), -NR 39 -(CH2) t (5-10 membered heteroaryl), -NR 39 -(CH2) t (C3~C 10 cycloalkyl) and -NR 39 -(CH2) t(4-10 membered heterocyclyl), where t is an integer from 0 to 4, e.g., 1 or 2, and each R 39 independently represent H or C1-C8 alkyl; any alkyl group present may itself be substituted by halo, substituted or unsubstituted amino, or hydroxy; any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present may itself be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. For the avoidance of doubt, the term "substituted amino" includes alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino groups, as defined below. Substituted amino encompasses both mono- and di-substituted amino groups.

[0051] "Carboxy" refers to the radical --C(O)OH.

[0052] "Cyano" refers to the -CN radical.

[0053] "Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, a halo group is fluoro or chloro.

[0054] "Hydroxy" refers to the -OH radical.

[0055] "Nitro" refers to the -NO2 radical.

[0056] "Cycloalkylalkyl" refers to an alkyl radical in which the alkyl group is substituted with 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.

[0057] "Heterocyclylalkyl" refers to an alkyl radical in which the alkyl group is substituted with a heterocyclyl group. Typical heterocyclylalkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, and the like.

[0058] "Thioketo" refers to the =S group.

[0059] As defined herein, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl groups). In general, the term "substituted," whether preceded by the term "optionally" or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that, when substituted, gives rise to a stable compound, e.g., a compound that does not undergo spontaneous transformation (e.g., by rearrangement, cyclization, elimination, or other reaction). Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents may be the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, any substituents described herein that result in stable compounds. The present invention contemplates any and all such combinations, provided that stable compounds are obtained. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents, as described herein, that satisfy the valence of the heteroatom and thereby form a stable moiety.

[0060] Exemplary carbon atom substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa、-CO2H、-CHO、-C(OR cc )2、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa, -P(=O)(R aa )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 Aryl and 5 and aryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd Is substituted with a group;

[0061] Or the two geminal hydrogens on a carbon atom are =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 radicals;

[0062] R aaEach occurrence of, independently, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R aa groups linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group;

[0063] R bb Each occurrence of is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14aryl and 5- to 14-membered heteroaryl, or two R bb groups linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group;

[0064] R cc Each occurrence of is independently hydrogen, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R cc groups linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group;

[0065] R dd Each occurrence of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NRff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C( =S)SR ee , -SC(=S)SR ee , -P(=O)2R ee , -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group or two geminal Rdd the substituents may be linked to form =O or =S;

[0066] R ee Each occurrence of, independently, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group;

[0067] R ff Each occurrence of is independently hydrogen, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, or two R ff groups linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg substituted with a group;

[0068] R gg Each occurrence of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 Alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C 1~6 alkyl)3 + X - , -NH(C 1~6 alkyl)2 + X- , -NH2(C 1~6 alkyl) + X - , -NH3 + X - , -N(OC 1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6 alkyl), -NH(OH), -SH, -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), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 alkyl), -SO2NH2, -SO2C 1~6 Alkyl, -SO2OC 1~6 Alkyl, -OSO2C1~6 Alkyl, -SOC 1~6 Alkyl, -Si(C 1~6 alkyl)3, -OSi(C 1~6 alkyl)3-C(=S)N(C 1~6 alkyl)2, C(=S)NH(C 1~6 alkyl), C(=S)NH2, -C(=O)S(C 1~6 alkyl), -C(=S)SC 1~6 Alkyl, -SC(=S)SC 1~6 Alkyl, -P(=O)2(C 1~6 alkyl), -P(=O)(C 1~6 alkyl)2, -OP(=O)(C 1~6 alkyl)2, -OP(=O)(OC 1~6 Alkyl)2, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl; or two geminal R gg The substituents may be linked to form =O or =S; where X - is the counter ion.

[0069] A "counterion" or "anionic counterion" is a negatively charged group associated with a cationic quaternary amino group to maintain electrical neutrality. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HSO4 - , SO4 -2Examples of such ions 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, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0070] Nitrogen atoms may be substituted or unsubstituted, where valence allows, and may include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14aryl and 5-14 membered heteroaryl, or two R cc The groups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with R aa , R bb , R cc and R dd is as defined above.

[0071] These and other exemplary substituents are described in detail in the detailed description, examples, and claims. It is not intended that the present invention be limited in any way by the exemplary recitation of substituents above. Other definitions

[0072] The term "pharmaceutically acceptable salt" refers to a salt that is suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66, 1-19. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic acids, inorganic bases, organic acids, 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 formed by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, sulphate, and the like. Examples of suitable salts include unosate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1~4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed where appropriate using counterions such as halides, hydroxides, carbonates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0073] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, e.g., mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs). In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0074] Disease, disorder, and condition are used interchangeably herein.

[0075] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions taken while a subject is suffering from a particular disease, disorder, or condition to lessen the severity of the disease, disorder, or condition or to delay or slow the progression of the disease, disorder, or condition ("therapeutic treatment"), and also actions taken before a subject begins to suffer from a particular disease, disorder, or condition ("prophylactic treatment").

[0076] Generally, the "effective amount" of a compound refers to an amount sufficient to induce a desired biological response. As will be understood by those skilled in the art, the effective amount of the compound of the present invention may vary depending on factors such as the desired biological goal, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the age, health status, and condition of the subject. The effective amount includes therapeutic treatment and prophylactic treatment.

[0077] As used herein, unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of the disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, an amount that reduces or avoids the symptoms or causes of a disease or condition, or an amount that enhances the therapeutic efficacy of another therapeutic agent.

[0078] As used herein, unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition, or to prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of the disease, disorder, or condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or an amount that enhances the prophylactic efficacy of another prophylactic agent. Abbreviation

[0079] AcCl: acetyl chloride; 9-BBN: 9-borabicyclo[3.3.1]nonane; BHT: 2,6-di-t-butyl-p-cresol (butylated hydroxytoluene); Boc: t-butoxycarbonyl; DCE: dichloroethane; DCM: dichloromethane; DMF: N,N-dimethylformamide; DMP: Dess-Martin periodinane; DMSO: dimethyl sulfoxide; EtOAc: ethyl acetate; i-PrMgCl: isopropyl magnesium chloride; MAD: methylaluminum bis(2,6-di-t-butyl-4-methylphenoxide); m-CPBA: metachloroperbenzoic acid; Me3SI: trimethylsulfonyl sulfonium iodide; MTBE: methyl tert-butyl ether; Na2SO4: sodium sulfate; n-BuLi: n-butyllithium; PCC: pyridinium chlorochromate; Pd(t-Bu3P)2: bis(tri-tert-butylphosphine)palladium(0); PE: petroleum ether; py: pyridine; TBAF: tetra-n-butylammonium fluoride; t-BuOK: potassium tert-butoxide; TBSCl: tert-butyl(chloro)dimethylsilane; TFA: trifluoroacetic acid; THF: tetrahydrofuran; Ts: p-toluenesulfonyl; (i-PrO)4Ti: titanium tetraisopropoxide. DETAILED DESCRIPTION OF THE INVENTION

[0080] Detailed Description of Specific Embodiments of the Invention As generally described above, the present invention provides novel oxysterols that are useful for preventing and / or treating a wide range of disorders, including, but not limited to, NMDA-mediated disorders. compound In one aspect, the compound of formula (IA): [ka] or a pharmaceutically acceptable salt thereof, wherein in formula (IA): A is carbocyclyl or heterocyclyl (e.g., unsubstituted or substituted carbocyclyl or heterocyclyl, e.g., heterocyclyl substituted with at least one heteroatom (e.g., 1, 2, or 3 heteroatoms)); R 1 is C 1~6 alkyl (e.g., -CH3 or -CH2CH3); R 5 is absent or hydrogen; [ka] represents a single or double bond, where one [ka] is a double bond, the other [ka] is a single bond, and R 5 does not exist. In one aspect, the compound of formula (IB): [ka] or a pharmaceutically acceptable salt thereof, wherein in formula (IB): 1 is hydrogen or C 1~6 alkyl (e.g., -CH3 or -CH2CH3); R 5 is absent or hydrogen; Z is —C(R A )2-, -NR B -, -O-, or -S-; X is a halogen, C 1~6 Alkyl, or -OR C and;R A is hydrogen, halogen, or C 1~6 alkyl; R B is hydrogen, C 1~6 Alkyl, -C(O)R C , -C(O)OR C , -C(O)N(RD )2, or -S(O)2R C and;R C is hydrogen or C 1~6 alkyl; each R D are independently hydrogen, C 1~6 m is an integer selected from 1, 2, and 3; n is an integer selected from 1, 2, and 3; p is an integer selected from 0, 1, 2, 3, 4, and 5; and [ka] represents a single or double bond, where one [ka] is a double bond, the other [ka] is a single bond, and R 5 does not exist. In some embodiments, the compound has Formula (II-A), Formula (II-B), or Formula (II-C): [ka] is a compound of In some embodiments, p is an integer selected from 0, 1, or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 1 and X is a halogen. In some embodiments, the compound has formula (II-D), formula (II-E), or formula (II-F): [ka] is a compound of In some embodiments, the compound has formula (II-G) or formula (II-H): [ka] [ka] is a compound of In some embodiments, the compound has formula (II-I) or formula (II-J): [ka] is a compound of In some embodiments, R 1 is C 1~6 In some embodiments, R 1 is methyl or ethyl. In some embodiments, R 1 are -CH3, -CF3, and -CH2CH3. In some embodiments, Z is —C(R A )2-, -O-, or -NR B Alternatively, Z is -CH2-. Alternatively, Z is O. Alternatively, Z is -NR B - where R B is -NH-, -N-(C1-C4 alkyl)-, or -NC(O)-(C1-C4 alkyl). In some embodiments, R A is halogen (e.g., —F). In some embodiments, Z is —CH 2 —, —CF 2 —, or —C(CH 3 ) 2 —. In some embodiments, the compound is: [ka] is. In some embodiments, the compound is: [ka] is. In some embodiments, Z is —O— or —NR B -It is. In some embodiments, the compound is: [ka] is. In some embodiments, the compound is: [ka] is. In some embodiments, the compound is: [ka] is. In some embodiments, Z is -NH-, -NMe-, or -NAc-. In some embodiments, the compound is: [ka] is. In some embodiments, Z is -CH2-. In some embodiments, Z is -C(CH3)2-. In some embodiments, Z is -CF2-. In some embodiments, m is 1, n is 2, and Z is -O-. In some embodiments, m is 2, and n is 2. In some embodiments, m is 3, and n is 1. In some embodiments, m is 3, n is 1, and Z is -O-. In some embodiments, m is 2, n is 2, and Z is -O- or -NR B -It is. In some embodiments, the compound is: [ka] [ka] [ka] is. In some embodiments, the compound is: [ka] [ka] [ka] is a pharmaceutically acceptable salt of Pharmaceutical Compositions

[0081] In another aspect, the present invention provides pharmaceutical compositions containing a pharmaceutically acceptable carrier and an effective amount of a compound as described herein (e.g., Formula (IA), (IB), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J)).

[0082] When used as pharmaceuticals, the compounds provided herein are typically administered in the form of a pharmaceutical composition, which can be prepared in a manner well known in the pharmaceutical arts and can contain at least one active compound.

[0083] In one embodiment, with respect to a pharmaceutical composition, the carrier is a parenteral carrier, an oral carrier, or a topical carrier.

[0084] The present invention also provides compounds as described herein (e.g., compounds of formula (IA), (II-B), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), (II-I), (II-J), (II-J), (II-K ... II), or (II-J)), or a pharmaceutical composition thereof.

[0085] Generally, the compounds provided herein are administered in an effective amount. The amount of compound actually administered is typically determined by a physician in light of the relevant circumstances, including the condition being treated, the selected route of administration, the actual compound being administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0086] The pharmaceutical compositions provided herein can be administered by various routes, including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Depending on the intended delivery route, the compounds provided herein are preferably formulated as either injectable or oral compositions, or as ointments, lotions, or patches (all for transdermal administration).

[0087] Compositions for oral administration can take the form of bulk liquid solutions or suspensions or bulk powders. However, more commonly, compositions are provided in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined amount of active ingredient calculated to produce a desired therapeutic effect, together with suitable pharmaceutical excipients. Typical unit dosage forms include pre-measured, pre-filled ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc., for solid compositions. In such compositions, the compound is usually a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder consisting of various vehicles or carriers and processing aids useful in forming the desired dosage form.

[0088] Liquid forms suitable for oral administration include buffers, suspensions and dispensing preparations. The formulation may comprise a suitable aqueous or non-aqueous vehicle containing additives, colorants, flavoring agents, etc. Solid forms may contain, for example, any of the following ingredients, or compounds of a similar nature: binders (e.g., microcrystalline cellulose, gum tragacanth, or gelatin); fillers (e.g., starch or lactose); disintegrating agents (e.g., alginic acid, Primogel, or corn starch); lubricants (e.g., magnesium stearate); glidants (e.g., colloidal silicon dioxide); sweetening agents (e.g., sucrose or saccharin); or flavoring agents (e.g., peppermint, methyl salicylate, or orange flavoring).

[0089] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. Conventionally, the active compound in such compositions is typically a minor component, often about 0.05 to 10% by weight, with the remainder being the injectable carrier and the like.

[0090] Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, more preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredient is typically combined with a paraffinic or water-miscible ointment base. Alternatively, the active ingredient can be formulated as a cream, for example, with an oil-in-water cream base. Such transdermal formulations are well known in the art and generally include additional ingredients that enhance the skin penetration or stability of the active ingredient or formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.

[0091] The compounds provided herein can also be administered by a transdermal device. Accordingly, transdermal administration can be via a transdermal device, either of the reservoir or porous membrane type or of a solid matrix variety. This can be achieved using a switch.

[0092] The components described above for orally administrable, injectable, or topically administrable compositions are merely representative. Other materials, processing techniques, and the like are set forth in Part 8 of Remington's Pharmaceutical Sciences, 17th Edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0093] The components described above for orally administrable, injectable, or topically administrable compositions are merely representative. Other materials, processing techniques, and the like are set forth in Part 8 of Remington's The Science and Practice of Pharmacy, 21st Edition, 2005, published by Lippincott Williams & Wilkins, which is incorporated herein by reference.

[0094] The compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0095] The present invention also relates to pharmaceutically acceptable formulations of compounds of Formula (I). In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, which consist of six, seven, and eight α-1,4-linked glucose units, respectively, optionally containing one or more substituents on the linked sugar moiety, including, but not limited to, methylation, hydroxyalkylation, acylation, and sulfoalkyl ether substitution. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, also known as Captisol®. See, e.g., U.S. Pat. No. 5,376,645. In certain embodiments, the formulation comprises hexapropyl-β-cyclodextrin. In further specific embodiments, the formulation comprises hexapropyl-β-cyclodextrin (e.g., 10-50% in water).

[0096] The present invention also relates to pharmaceutically acceptable acid addition salts of the compounds 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 pharmacologically acceptable anions (e.g., hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, and the like).

[0097] The following formulation examples illustrate representative pharmaceutical compositions that may be prepared in accordance with the present invention, although the present invention is not limited to the following pharmaceutical compositions.

[0098] Exemplary Formulation 1—Tablets: A compound of Formula (IA), or a pharmaceutically acceptable salt thereof, can be blended as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A trace amount of magnesium stearate is added as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg of active compound per tablet) in a tablet press.

[0099] Exemplary Formulation 2—Capsules: The compound of formula (IA), or a pharmaceutically acceptable salt thereof, can be admixed as a dry powder with a starch diluent in an approximate 1:1 weight ratio. Fill into 250 mg capsules (125 mg of active compound per capsule).

[0100] Exemplary Formulation 3 - Liquid: The compound of formula (IA), or a pharmaceutically acceptable salt thereof (125 mg), can be mixed with sucrose (1.75 g) and xanthan gum (4 mg), the resulting mixture can be blended and passed through a No. 10 mesh US sieve, and then mixed with a previously prepared aqueous solution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50 mg). Sodium benzoate (10 mg), flavor, and color can be diluted with water and added with stirring. Sufficient water can then be added to bring the total volume to 5 mL.

[0101] Exemplary Formulation 4—Tablets: A compound of Formula (IA), or a pharmaceutically acceptable salt thereof, can be blended as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A trace amount of magnesium stearate is added as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg of active compound) in a tablet press.

[0102] Exemplary Formulation 5—Injection: A compound of formula (IA), or a pharmaceutically acceptable salt thereof, can be dissolved or suspended in a sterile buffered saline injectable aqueous medium to a concentration of approximately 5 mg / mL.

[0103] Exemplary Formulation 6—Tablets: A compound of Formula (IA), or a pharmaceutically acceptable salt thereof, can be blended as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A trace amount of magnesium stearate is added as a lubricant. The mixture is formed into 90-150 mg tablets (30-50 mg of active compound per tablet) in a tablet press.

[0104] Exemplary Formulation 7—Tablets: A compound of Formula (IA), or a pharmaceutically acceptable salt thereof, can be blended as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A trace amount of magnesium stearate is added as a lubricant. The mixture is formed into 30-90 mg tablets (10-30 mg of active compound per tablet) in a tablet press.

[0105] Exemplary Formulation 8—Tablets: A compound of Formula (IA), or a pharmaceutically acceptable salt thereof, can be blended as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A trace amount of magnesium stearate is added as a lubricant. The mixture is formed into 0.3-30 mg tablets (0.1-10 mg of active compound per tablet) in a tablet press.

[0106] Exemplary Formulation 9—Tablets: A compound of Formula (IA), or a pharmaceutically acceptable salt thereof, can be blended as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A trace amount of magnesium stearate is added as a lubricant. The mixture is formed into 150-240 mg tablets (50-80 mg of active compound per tablet) in a tablet press.

[0107] Exemplary Formulation 10—Tablets: A compound of Formula (IA), or a pharmaceutically acceptable salt thereof, can be blended as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A trace amount of magnesium stearate is added as a lubricant. The mixture is formed into 270-450 mg tablets (90-150 mg of active compound per tablet) in a tablet press.

[0108] Injectable dose levels range from about 0.1 mg / kg / hour to at least 10 mg / kg / hour, all over a period of about 1 to about 120 hours, particularly 24 to 96 hours. A preloading bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady-state levels. The maximum total dose is not expected to exceed about 2 g / day for a 40-80 kg human patient.

[0109] For the prevention and / or treatment of long-term conditions, the regimen usually extends over many months or years, and oral administration is preferred for patient convenience and tolerance. For oral administration, oral administration 1 to 5 times per day, particularly 2 to 4 times per day, typically 3 times per day is a typical regimen. Using these dosing patterns, each dose provides about 0.01 to about 20 mg / kg of a compound provided herein, with preferred doses providing about 0.1 to about 10 mg / kg, particularly about 1 to about 5 mg / kg, respectively.

[0110] Transdermal administration is generally selected to provide blood levels similar to or lower than those achieved using injection administration.

[0111] When used to prevent the occurrence of CNS disorders, the compounds provided herein can typically be administered to subjects at risk of developing the condition at the dosage levels described above, under the advice and supervision of a physician. Subjects at risk of developing a particular condition generally include subjects with a family history of the condition, or subjects identified by genetic testing or screening as being particularly susceptible to developing the condition. Treatment Methods and Uses

[0112] The compounds of the invention (e.g., compounds of Formula (IA), (IB), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J), and pharmaceutically acceptable salts thereof), as described herein, are generally designed to modulate NMDA function and thus act as oxysterols for the treatment and prevention of, for example, CNS-related conditions in a subject. In some embodiments, the compounds described herein (e.g., compounds of Formula (IA), (IB), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J), and pharmaceutically acceptable salts thereof), as described herein, are generally designed to penetrate the blood-brain barrier (e.g., designed to be transported across the blood-brain barrier). Modulation, as used herein, refers, for example, to the inhibition or potentiation of NMDA receptor function. In certain embodiments, a compound of Formula (IA), (IB), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J), or a pharmaceutically acceptable salt thereof, can act as a negative allosteric modulator of NMDA (NAM) and inhibit NMDA receptor function. In certain embodiments, the present invention (e.g., a compound of Formula (IA), (IB), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J), or a pharmaceutically acceptable salt thereof) can act as a positive allosteric modulator of NMDA (PAM) and synergize NMDA receptor function.In certain embodiments, a compound of Formula (IA), (IB), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J), or a pharmaceutically acceptable salt thereof, modulates NMDA function but does not act as a negative allosteric modulator (NAM) or a positive allosteric modulator (PAM) of NMDA.

[0113] In some embodiments, the disorder is cancer. In some embodiments, the disorder is diabetes. In some embodiments, the disorder is a metabolic disorder. In some embodiments, the disorder is a sterol synthesis disorder. In some embodiments, the disorder is a gastrointestinal (GI) disorder, such as constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) (e.g., ulcerative colitis, Crohn's disease), or other conditions affecting the GI tract. In some embodiments, the disorder is an inflammatory bowel disease, an anal structural disorder (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas), colon polyps, cancer, or colitis.

[0114] In some embodiments, the disorder is Smith-Lemli-Opitz syndrome (SLOS). In some embodiments, the disorder is desmosterolosis. In some embodiments, the disorder is sitosterolemia. In some embodiments, the disorder is cerebrotendinous xanthomatosis (CTX). In some embodiments, the disorder is mevalonate kinase deficiency (MKD). In some embodiments, the disorder is a 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.

[0115] Exemplary conditions associated with NMDA modulation include, but are not limited to, gastrointestinal (GI) disorders (e.g., constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) (e.g., ulcerative colitis, Crohn's disease), structural disorders affecting the GI, anal disorders (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas), colon polyps, cancer, colitis), and CNS conditions (e.g., as described herein).

[0116] Exemplary CNS conditions associated with NMDA modulation include adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, social phobia, generalized anxiety disorder), cognitive disorders (including Alzheimer's disease and other forms of dementia), dissociative disorders, eating disorders, mood disorders (including depression (e.g., postpartum depression), bipolar disorder, dysthymic disorder, suicidality), schizophrenia or other psychotic disorders (including schizoaffective psychosis), sleep disorders (including insomnia), substance abuse-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorder, and the like. These include, but are not limited to, cerebral disorders (including those involving mutations in the Shank family of proteins (e.g., Shank3)), neurodevelopmental disorders (including Rett syndrome), multiple sclerosis, sterol synthesis disorders, pain (including acute and chronic pain), seizure disorders (including status epilepticus and monogenic forms of epilepsy, such as Dravet disease and tuberous sclerosis complex (TSC)), stroke, traumatic brain injury, movement disorders (including Huntington's disease and Parkinson's disease), and tinnitus. In certain embodiments, the compounds of the present invention (e.g., compounds of Formula (IA), (IB), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J), or a pharmaceutically acceptable salt thereof) can be used to induce sedation or anesthesia. In certain embodiments, a compound of Formula (IA), (IB), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J), or a pharmaceutically acceptable salt thereof, is useful in the treatment or prevention of adjustment disorders, anxiety disorders, cognitive disorders, dissociative disorders, eating disorders, mood disorders, schizophrenia or other psychotic disorders, sleep disorders, substance-related disorders, personality disorders, autism spectrum disorders, neurodevelopmental disorders, sterol synthesis disorders, pain, seizure disorders, stroke, traumatic brain injury, movement and visual disorders, hearing disorders, and tinnitus.

[0117] In another aspect, a method is provided for treating or preventing brain excitability in a subject suspected of or afflicted with a condition associated with brain excitability, comprising administering to the subject an effective amount of a compound of the invention (e.g., a compound of Formula (IA), (IB), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J), or a pharmaceutically acceptable salt thereof). The method includes administering a compound (sodium salt) to the patient.

[0118] In yet another aspect, provided is a combination of a compound of the present invention (e.g., a compound of Formula (IA), (IB), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J), or a pharmaceutically acceptable salt thereof) with another pharmacologically active agent. The compounds provided herein can be administered as the sole active agent or in combination with other agents. Administration in combination can proceed by any technique apparent to one skilled in the art, such as separate, sequential, simultaneous, and alternating administration. Diseases and Disorders Methods for treating sterol synthesis disorders are described herein. Exemplary disorders are described herein. The methods include administering an NMDA receptor modulating compound to a subject, e.g., a subject suffering from a sterol synthesis disorder, such as SLOS. Exemplary compounds are described herein. Impaired sterol synthesis

[0119] In one aspect, a method for treating a sterol synthesis disorder is described herein. Cholesterol plays an essential role in growth and development. Cholesterol is a membrane lipid and a precursor of many molecules that play important roles in cell growth and differentiation, protein glycosylation, and signal transduction pathways. Several enzymes and intermediates are involved in the biosynthesis of cholesterol. Disorders caused by deficiency in any enzyme involved in cholesterol biosynthesis result in the accumulation of intermediates and imbalances of biomolecules, leading to disorders such as congenital skeletal malformations, dysmorphic facial features, psychomotor retardation, and growth disorders. In some embodiments, a sterol synthesis disorder or a symptom of a sterol synthesis disorder can be treated by administering a compound described herein (e.g., an NMDA receptor modulating compound as described herein) to a subject suffering from a sterol synthesis disorder. Additional disorders are described below. Smith-Lemli-Opitz syndrome

[0120] In one aspect, methods for treating Smith-Lemli-Opitz syndrome (or SLOS, or 7-dehydrocholesterol reductase deficiency) are described herein. SLOS is a congenital abnormality 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, the disease is characterized by low levels of cerebrosterol (24(S)-hydroxycholesterol). SLOS is an autosomal recessive genetic condition resulting from a deficiency in the last enzyme in the cholesterol synthesis pathway, resulting in low or low-to-normal levels of plasma cholesterol and elevated levels of 7- and 8-dehydrocholesterol (DHC; 7DHC and 8DHC). Common treatments currently in use include dietary cholesterol supplementation, treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HMG CoA reductase inhibitors, also known as statins), and treatment with agents that increase cholesterol production and / or accumulation; and reducing the accumulation of the potentially toxic cholesterol precursors 7DHC and 8DHC. Desmosterolosis

[0121] Desmosterolosis is a deficiency of desmosterol reductase and has a phenotype similar to SLOS. In one aspect, described herein are methods for treating desmosterolosis with the compounds described herein. Sitosterolemia

[0122] 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 intestine. Patients usually exhibit tendon xanthomas and tuberous xanthomas and premature coronary artery disease. In one aspect, methods for treating sitosterolemia with the compounds described herein are described herein. Cerebrotendinous xanthomatosis (CTX)

[0123] In one aspect, described herein are methods for treating cerebrotendinous xanthomatosis (also known as cerebral cholesterolosis or Van Bogaert-Scherer-Epstein syndrome) with the compounds described herein. CTX can be caused by mutations in the CYP27A1 gene, which produces the sterol 27-hydroxylase enzyme. Sterol 27-hydroxylase metabolizes cholesterol into bile acids (e.g., chenodeoxycholic acid), which are important in the absorption of fat in the intestine. Enzyme dysfunction can lead to cholesterol accumulation in tissues. CTX is characterized by diarrhea in children and cataracts, tendon xanthomas, reduced mental ability, and abnormal movements in adults. Mevalonate kinase deficiency syndrome (MKD)

[0124] Mevalonate kinase deficiency, also called mevalonic aciduria (a more severe form of MKD) or hyper-IgD syndrome with periodic fever syndrome (HIDS, or hyperglobulin Demia, a more benign form of MKD), causes accumulation of mevalonic acid in the urine as a result of insufficient activity of mevalonate kinase. MKD can result in developmental delay, hypotonia, anemia, hepatosplenomegaly, dysmorphic features, mental retardation, and general growth failure. Mevalonic aciduria is characterized by delayed physical and mental development, failure to thrive, recurrent episodes of fever accompanied by vomiting and diarrhea, enlarged liver, spleen, and lymph nodes, microcephaly (small head size), cataracts, hypotonia, short stature, distinctive facial features, ataxia, and anemia. HIDS is characterized by recurrent episodes of fever accompanied by enlarged lymph nodes, joint pain, gastrointestinal problems, and rash. In one aspect, described herein are methods for treating MKD with the compounds described herein. SC4MOL gene mutation (SMO deficiency)

[0125] SC4MOL gene deficiency is a genetic disorder in the cholesterol biosynthesis pathway (for example, 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 skin fibroblasts. In one aspect, the present invention provides a method for treating SMO deficiency with the compounds described herein. Niemann-Pick disease

[0126] Niemann-Pick disease is a lysosomal storage disorder caused by a genetic mutation that affects metabolism. Niemann-Pick disease results from the body's inability to transport cholesterol and other fatty substances (lipids), leading to their abnormal buildup. This buildup can be damaging to affected areas. autism

[0127] In one aspect, a method for treating autism spectrum disorder or autism is described herein. Autism spectrum disorder (ASD) and autism refer to a group of complex disorders of brain development. Autism usually involves impaired social interaction, e.g., language. Autism is characterized by difficulties with verbal and non-verbal communication. Individuals with autism often exhibit repetitive behaviors. Autism may be accompanied by intellectual disability, difficulties with motor coordination and attention, and physical health problems, such as sleep disorders and gastrointestinal disorders. Individuals with autism may also excel in visual skills, music, mathematics, and art. Autism can refer to autistic disorder, childhood disintegrative disorder, pervasive developmental disorder not otherwise specified (PDD-NOS), and Asperger's syndrome. Autism also refers to monogenic autism, such as synaptopathies, e.g., Rett syndrome, Fragile X syndrome, and Angelman syndrome. Phenyletonuria-related disorders

[0128] In one aspect, the present invention provides a method for treating disorders (e.g., cognitive impairment) associated with phenylketonuria with the compounds described herein. Phenylketonuria can lead to hypocholesterolemia and hypovitaminosis D. Compared with subjects without phenylketonuria, total cholesterol, low-density cholesterol, and 25-hydroxyvitamin D have been found to be reduced in subjects with phenylketonuria (Clin.Chim.Acta 2013,416:54-59). 24S-hydroxycholesterol, 27S-hydroxycholesterol, and 7α-hydroxycholesterol (e.g., representing peripheral and hepatic cholesterol excretion, respectively) have been shown to be significantly reduced in subjects with phenylketonuria, while 7β-hydroxycholesterol (e.g., reflecting oxidative stress) has been significantly increased in subjects with phenylketonuria. Changes in 24S-OHC and 7β-hydroxycholesterol levels correlate with phenylalanine levels, and 27S-hydroxycholesterol levels can correlate with 25-hydroxyvitamin D levels in subjects with phenylketonuria. Alternative Embodiments In alternative embodiments, compounds described herein (e.g., compounds of formula (IA), (IB), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J)) may also include one or more isotopic substitutions. In some embodiments, hydrogen is 2 H (D or deuterium), or 3 H (T or tritium). In some embodiments, carbon can be 13 C or 14 C. In some embodiments, oxygen is 18 In some embodiments, nitrogen may be 15In further embodiments, the compounds may contain one or more isotopic substitutions, where the sites of isotopic substitution are enriched with a particular isotope. For example, the compounds described herein may be 2 H or 3 Enriched hydrogen as H, 13 C or 14 Carbon enriched as C, 18 Oxygen enriched as O, or 15 It may contain enriched nitrogen as N. [Example]

[0129] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described herein are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and are not to be construed in any way as limiting the scope thereof. material and method

[0130] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, although it is understood that other process conditions can also be used unless otherwise stated. Optimal reaction conditions are: Although they may vary depending on the particular reactants or solvents used, such conditions can be determined by one skilled in the art by routine optimization.

[0131] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The selection of a suitable protecting group for a particular functional group and suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups and their introduction and removal are described in T.W. Greene and P.G.M. Buts, Protecting Groups in Organic Synthesis, 2nd Edition, Wiley, New York, 1991, and the references cited therein.

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

[0133] Exemplary general method for preparative HPLC: Column: Waters RBridge prep 10 μm C18, 19×250 mm. Mobile phase: Acetonitrile, water (NH4HCO3) (30 L water, 24 g NH4HCO3, 30 mL NH3.H2O). Flow rate: 25 mL / min.

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

[0135] NMDA potentiation was assessed using whole-cell patch clamp of mammalian cells expressing NMDA receptors. Whole-cell patch clamping of mammalian cells (Ionworks Barracuda (IWB) The whole-cell patch clamp technique was used to investigate the effects of the compounds on GlunN1 / GluN2A glutamate receptors expressed in mammalian cells, and the results are shown in Table 1. HEK293 cells were transformed with adenovirus 5 DNA and transfected with cDNA encoding the human GRIN1 / GRIN2A gene. Stable transfectants were selected using G418 and Zeocin resistance genes incorporated into the expression plasmid, and selection pressure was maintained with G418 and Zeocin in the medium. Cells were grown in Dulbecco's modified erythrocyte sedimentation medium supplemented with 10% fetal bovine serum, 100 μg / ml penicillin G sodium, 100 μg / ml streptomycin sulfate, 100 μg / ml Zeocin, 5 μg / ml blasticidin, and 500 μg / ml G418. They were cultured in Eagle's medium / nutrient mixture (D-MEM / F-12). The effects of test articles were evaluated in an 8-point concentration response format (quadruplicate wells / concentration). All test and control solutions contained 0.3% DMSO and 0.01% Kolliphor® EL (C5135, Sigma). Test article formulations were loaded into 384-well compound plates using an automated liquid handling system (SciClone ALH3000, Caliper LifeSciences). Measurements were performed using the IonWorks Barracuda platform according to the following 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; pH adjusted to 7.4 with NaOH (refrigerated until use). c) Holding potential: -70 mV, potential during agonist / PAM amplification: -40 mV. Recording Procedure: a) Extracellular buffer is loaded into PPC plate wells (11 μL per well). Cell suspension is pipetted into the wells of the PPC planar electrodes (9 μL per well). b) The whole-cell recording configuration is established by patch perforation and membrane currents are recorded by an on-board patch clamp amplifier. c) Two recordings (scans) are made: one during pre-amplification of the test article alone (pre-amplification duration - 5 minutes) and the second during pre-amplification of the test article and agonist (EC 20 L-glutamate and 30 μM glycine) to detect the positive modulatory effects of the test article. Test article administration: The first preapplication consisted of the addition of 20 μL of a 2x concentrated test article solution, and the second of 20 μL of a 1x concentrated test article and agonist at 10 μL / s (total application time of 2 seconds).

[0136] Synthesis method Example 1. Synthesis of intermediate A-6. [ka] Step 1. Synthesis of Intermediate A-1. To a suspension of PPh3MeBr (2.13 kg, 5.97 mol) in THF (3000 mL) was added t-BuOK (688 g, 6.14 mol) at 20°C. The color of the suspension changed to yellow. After stirring at 50°C for 1 h, pregnenolone (630 g, 2.05 mol) was added at 50°C, and the reaction mixture was stirred at 50°C for 2 h. After cooling to 20°C, the mixture was treated with NH4Cl (10% aqueous solution, 5 L) and heptane (3.5 L) and stirred for 15 min. The organic layer was separated and concentrated in vacuo to give the crude material as a thick oil, which was poured into MTBE (10 L) with vigorous stirring and stirred at room temperature for 16 h. The resulting off-white The white solid was collected by filtration and washed with MTBE (3 L). The combined filtrates were mixed with MeOH (10 L) and concentrated in vacuo to 6 L. The resulting off-white solid was collected by filtration, washed with MeOH (3 L), and air-dried to give 700 g of a damp off-white solid. The combined MeOH filtrates were concentrated in vacuo to give a thick oil. This oil was poured into MTBE (3 L) with vigorous stirring, and the mixture was stirred for 3 hours. The resulting white solid was collected by filtration and washed with MTBE (1 L). The combined filtrates were mixed with MeOH (3 L) and concentrated in vacuo to 1.5 L. The resulting white solid was collected by filtration, washed with MeOH (500 mL), and air-dried to give 150 g of a damp off-white solid. The previous 700 g and 150 g batches were combined and dried under vacuum to give Intermediate A-1 (552 g, 88%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 5.40-5.30 (m, 1H), 4.85 (s, 1H), 4.71 (s, 1H), 3.60-3.50 (m, 1H), 2.36-2.18 (m, 2H), 2.08-1.96 (m, 2H), 1.92-1.78 (m, 3H), 1.76 (s, 3H), 1.73-1.48 (m, 9H), 1.38-1.03 (m, 4H), 1.01 (s, 3H), 1.00-0.91 (m, 1H), 0.58 (s, 3H).

[0137] Step 2. Synthesis of Intermediate A-2. To a solution of Intermediate A-1 (184 g, 585 mmol) in DCM (2000 mL) was added DMP (496 g, 1.17 mol) portionwise at 25 °C, followed by water (42 mL). The mixture was stirred at 25 °C for 30 minutes. Water (1500 mL) and NaHCO (750 g) were added portionwise (gas evolution was observed). The mixture was filtered through a pad of Celite, and the solid was washed with DCM (500 mL). The organic layer of the filtrate was separated, washed with NaSO (1000 mL, saturated), dried over NaSO, filtered, and concentrated in vacuo below 30 °C to give Intermediate A-2 (250 g, crude) as a light yellow gum. The crude product was used directly in the next step without further purification or analysis.

[0138] Step 3. Synthesis of Intermediate A-3. To a solution of BHT (769 g, 3.49 mol) in toluene (1500 mL), AlMe3 (870 mL, 2 M in toluene, 1.74 mol) was added at 0 °C. After stirring at 0 °C for 1 h, the reaction mixture was cooled to -78 °C, and a solution of Intermediate A-2 (250 g crude, theoretical mass: 182 g, 582 mmol) in toluene (1000 mL) was added. After stirring at -78 °C for 1 h, MeMgBr (580 mL, 3 M in ether, 1.74 mmol) was added, and the mixture was stirred at -78 °C for another 1 h. The mixture was quenched by pouring it in portions into citric acid (4000 mL, 20% aqueous solution) (gas evolution was observed). Two other batches were performed and combined. The mixture was extracted with EtOAc (10 L). The organic layer was separated, washed with brine (5 L, 10%), NaHCO (5 L, saturated aqueous solution), brine (5 L, saturated), dried over NaSO, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE to EtOAc) to give Intermediate A-3 (440 g, impure, containing Intermediate A-1) as a light yellow solid. To a solution of impure Intermediate A-3 (440 g) in DCM (6 L) was added DMAP (24.4 g) and AcO (51 g). The mixture was stirred at 20 °C for 1 h. NaHCO (1 L, saturated aqueous solution) was added, and the mixture was stirred for 10 min. The organic layer was separated, concentrated in vacuo, and the residue was triturated with PE (2 L). The solid was washed with PE (3 × 500 mL) and dried in vacuo to give A-3 (262 g) as an off-white solid. The combined filtrate was concentrated, purified by silica gel chromatography (PE / EtOAc=50 / 1 to 8 / 1), and triturated with PE (1 L) to give A-3 (30 g). The total yield for the two steps was 51%. 1H NMR (400 MHz, CDCl3) δ 5.35-5.28 (m, 1H), 4.85 (s, 1H), 4.71 (s, 1H), 2.48-2.37 (m, 1H), 2.08-1.94 (m, 3H), 1.92-1.85 (m, 1H), 1.82-1.33 (m, 14H), 1.29-1.08 (m, 7H), 1.02 (s, 3H), 1.00-0.93 (m, 1H), 0 .59 (s, 3H).

[0139] Step 4. Synthesis of Intermediate A-4. Intermediate A-3 (100 g, 304 mmol) was dissolved in 9-BBN (1.21 L, 0.5 M in THF, 608 mmol) at 0 °C under N2. The solution was heated and stirred at 65 °C for 1 hour and then cooled again to 10 °C, resulting in the formation of an off-white precipitate. Ethanol (279 g, 6080 mmol) and aqueous NaOH (304 mL, 5 M, 1520 mmol) were added dropwise below 10 °C to give a clear solution. Hydrogen peroxide (343 g, 30% in water, 3040 mmol) was added dropwise below 10 °C, and the reaction mixture was heated and stirred at 75 °C for 1 hour. The mixture was cooled to 20 °C, and the resulting off-white precipitate was collected by filtration. The filter cake was washed with water (3×500 mL) and dried in vacuo to give an off-white solid, which was triturated with refluxing ethanol (1.5 L) to give intermediate A-4 (92 g, 88%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 5.31-5.29 (m, 1H), 3.65-3.63 (m, 1H), 3.38-3.37 (m, 1H), 2.42 (d, J = 12.4, 1H), 2.05-1.92 (m, 3H), 1.88-1.63 (m, 4H), 1.63-1.40 (m, 8H), 1.40-0.90 (m, 16H), 0.70 (s, 3H).

[0140] Step 5. Synthesis of Intermediate A-5. To a solution of Intermediate A-4 (124.5 g, 357 mmol) in chloroform (1 L) and pyridine (700 mL) was added TsCl (204 g, 1071 mmol) at 15° C., and the mixture was stirred at 15° C. for 2 hours. The mixture was concentrated under reduced pressure to remove most of the chloroform. The pyridine mixture was poured into water (6 L), and the resulting off-white solid was collected by filtration, and the filter cake was washed with water (6×1 L). The off-white solid was dissolved in DCM (3.5 L), dried over NaSO, filtered, and concentrated under reduced pressure to give Intermediate A-5 (163 g, 92%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 5.29-5.28 (m, 1H), 3.96 (dd, J = 3.2, 9.6 Hz, 1H), 3.79 (dd, J = 6.4, 9.2 Hz, 1H), 2.45 (s, 3H), 2.41 (d, J = 13.6 Hz, 1H), 1.99-1.91 (m, 3H), 1.77-1.39 (m, 11H), 1.26-0.86 (m, 16H), 0.64 (s, 3H).

[0141] Step 6. Synthesis of Intermediate A-6. To a solution of Intermediate A-5 (163 g, 325 mmol) in DMF (1.7 L) was added KI (258 g, 1560 mmol) at 15° C. The mixture was heated and stirred at 60° C. for 2 hours. Sodium benzenesulfinate (195 g, 975 mmol) was added, and stirring was continued at 60° C. for 2 hours. The reaction mixture was cooled to 25° C. and combined with another batch of 83 g of Intermediate A-5. The combined mixture was poured into water (20 L) to give a yellow solid, which was collected by filtration and washed with water (3×2 L). The resulting filter cake was dissolved in DCM (5 L), washed with water (2 × 1 L), brine (2 × 1 L), dried over NaSO, filtered, and concentrated in vacuo to give a yellow solid residue, which was recrystallized from toluene (2.5 L) to give intermediate A-6 (150 g, 65%) as a light yellow solid. The recrystallization filtrate was concentrated in vacuo to give crude intermediate A-6 (30 g) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 7.2 Hz, 2H), 7.69-7.61 (m, 1H), 7.60-7.50 (m, 2H), 5.28-5.27 (m, 1H), 3.14 (d, J = 14.0 Hz, 1H), 2.85 (dd, J = 9.6, 14.0 Hz, 1H), 2.41 (d, J = 12.8 Hz, 1H), 2.17-2.03 (m, 1H), 2.02-1.87 (m, 3H), 1.81-1.65 (m, 3H), 1.60-1.32 (m, 8H), 1.25-0.85 (m, 15H), 0.65 (s, 3H). LCMS 3.0 min chromatography: Rt = 2.057 min, 30-90 AB, MS ESI C 29 H 41 O2S [M+H-H2O] + Calculated value: 453, measured value: 453.

[0142] Example 2. Synthesis of intermediate B-4. [ka] Step 1. Synthesis of Intermediate B-1. To a solution of BHT (191 g, 866 mmol) in toluene (500 mL) was added AlMe3 (2 M in toluene, 216 mL, 433 mmol) at 10° C., and the solution was stirred for 1 hour. To this mixture was added a solution of Intermediate A-2 (theoretical mass: 44.6 g) in DCM (100 mL) at −78° C. The mixture was stirred at −78° C. for 1 hour. EtMgBr (141 mL, 426 mmol) was added at −78° C., and the mixture was stirred at −78° C. for 20 minutes. Saturated citric acid (1 L) was added. The organic phase was separated, washed with brine (600 mL), dried over NaSO, and concentrated in vacuo to give a residue, which was purified by column chromatography on silica gel (PE: EtOAc = 50:1 to 30:1) to give intermediate B-1 (27 g, 55%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 5.35-5.25 (m, 1H), 4.85 (s, 1H), 4.71 (s, 1H), 2.40-2.30 (m, 1H), 2.10-1.60 (m, 14H), 1.50-0.75 (m, 17H), 0.58 (s, 3H).

[0143] Step 2. Synthesis of Intermediate B-2. To 9-BBN (200 mL, 0.5 M in THF, 100 mL) was added Intermediate B-1 (13 g, 37.9 mmol) at 0 °C under N. The mixture was heated and stirred at 65 °C for 2 h, then cooled to 10 °C. EtOH (46.5 g) was added, followed by aqueous NaOH (51 mL, 5 M) and HO (57 g, 30% in water), and the resulting mixture was stirred at 75 °C for 1 h. The mixture was concentrated in vacuo to give a solution (100 mL), which was extracted with EtOAc (2 × 150 mL), washed with NH4Cl (2 × 300 mL) and brine (2 × 300 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue, which was purified by column chromatography on silica gel (PE: EtOAc = 50:1 to 3:1) to give intermediate B-2 (9.86 g, 72%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 5.31-5.29 (m, 1H), 3.70-3.60 (m, 1H), 3.40-3.30 (m, 1H), 2.40-2.30 (m, 1H), 2.10-1.90 (m, 3H), 1.75-1.65 (m, 1H), 1.65-1.55 (m, 2H), 1.50-1.26 (m, 6H), 1.25-0.95 (m, 15H), 0.90-0.75 (m, 6H), 0.70 (s, 3H).

[0144] Step 3. Synthesis of Intermediate B-3. To a solution of Intermediate B-2 (9.86 g, 27.3 mmol) in CHCl (100 mL) and pyridine (20 mL) was added TsCl (15.6 g, 81.9 mmol) at 15° C. The mixture was stirred at 15° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give 60 mL of a mixture, which was poured into 600 mL of water to give an off-white precipitate. The mixture was filtered, and the filter cake was washed with water, dissolved in DCM (150 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give Intermediate B-3 as an off-white solid (9.9 g, 70%). 1 H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 5.30-5.20 (m, 1H), 4.00-3.90 (m, 1H), 3.80-3.70 (m, 1H), 2.45 (s, 3H), 2.40-2.30 (m, 1H), 2.10-1.90 (m, 3H), 1.75-1.60 (m, 6H), 1.55-1.30 (m, 5H), 1.25-0.95 (m, 13H), 0.90-0.80 (m, 5H), 0.65-0.50 (m, 3H).

[0145] Step 4. Synthesis of Intermediate B-4. To a solution of intermediate B-3 (9.9 g, 19.2 mmol) in DMF (150 mL) was added KI (15.2 g, 92.1 mmol) at 15 °C. The mixture was heated and stirred at 60 °C for 2 h. Sodium benzenesulfinate (9.43 g, 57.5 mmol) was added, and the mixture was stirred at 60 °C for 2 h. The mixture was poured into water (200 mL), and the resulting yellow precipitate was collected by filtration. The filter cake was washed with water (2 × 100 L), dissolved in DCM (500 mL), washed with water (2 × 500 mL) and brine (2 × 1 L), dried over NaSO, filtered, and concentrated in vacuo to give a yellow solid residue, which was purified by silica gel chromatography (0 to 35% EtOAc in PE) to give intermediate B-4 (8 g, 89%). 1 H NMR (400 MHz, CDCl3) δ 7.95-7.88 (m, 2H), 7.68-7.62 (m, 1H), 7.61-7.53 (m, 2H), 5.30-5.22 (m, 1H), 3.20-3.08 (m, 1H), 2.91-2.79 (m, 1H), 2.40-2.30 (m, 1H), 2.09-1.87 (m, 4H), 1.74-1.60 (m, 4H), 1.50-1.36 (m, 7H), 1.24-0.98 (m, 13H), 0.90-0.80 (m, 4H), 0.65 (s, 3H).

[0146] Example 3. Synthesis of intermediate C-8. [ka] Step 1. Synthesis of Intermediate C-1. To a solution of Intermediate A-1 (4 kg, 12.7 mol) in DCM (30 L) was added imidazole (1.72 kg, 25.4 mol) and TBSCl (2.86 kg, 19.0 mol) at 25° C. After stirring at 25° C. for 16 h, water (10 L) was added, and the organic phase was separated and concentrated to give a residue that was triturated with refluxing MeOH (15 L) to give Intermediate C-1 (5.02 kg, 92%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 5.38-5.28 (m, 1H), 4.85 (s, 1H), 4.71 (s, 1H), 3.57-3.41 (m, 1H), 2.33-2.11 (m, 2H), 2.10-1.94 (m, 2H), 1.90-1.61 (m, 8H), 1.60-1.38 (m, 6H), 1.28-1.03 (m, 4H), 1.00 (s, 3H), 0.98-0.91 (m, 1H), 0.89 (s, 9H), 0.58 (s, 3H), 0.06 (s, 6H).

[0147] Step 2. Synthesis of Intermediate C-2. To a solution of Intermediate C-1 (1.69 kg, 3.94 mol) in THF (8 L) was added 9-BBN dimer (671 g, 2.75 mol), and the resulting mixture was stirred at 25 °C under N for 1 h (the formation of an off-white precipitate was observed). Ethanol (2.26 L, 39.4 mol) and NaOH (3.94 L, 5 M, 19.7 mol) were added, and the resulting clear solution was treated dropwise with HO (3.94 L, 10 M, 39.4 mol) at 25 °C (the internal temperature rose to reflux). After the addition was complete, the mixture was cooled to 25 °C and stirred for 16 h, after which NaSO (2.5 L, 20% aqueous solution) and water (5 L) were added at 25 °C. After stirring for 1 h, the mixture was allowed to settle to form a clear lower layer and a suspended upper layer. The upper suspension layer was collected and treated with water (20 L). The mixture was stirred for 15 minutes and filtered. The solid was washed with water until the pH was <9 to give the wet product, which was combined with two other batches of product from the previous synthesis. The wet product was dissolved in DCM (100 L) and the organic layer was separated, dried over Na2SO4, filtered, and concentrated to 20 L. The residue was used directly in the next step. 1 H NMR (400 MHz, CDCl3) δ 5.40-5.23 (m, 1H), 3.70-3.60 (m, 1H), 3.55-3.42 (m, 1H), 3.41-3.31 (m, 1H), 2.31-2.20 (m, 1H), 2.20-2.11 (m, 1H), 2.06-1.91 (m, 2H), 1.89-1.67 (m, 3H), 1.65-1.39 (m, 7H), 1.38-1.08 (m, 6H), 1.05 (d, J = 6.4 Hz, 3H), 1.00 (s, 3H), 0.99-0.91 (m, 2H), 0.88 (s, 9H), 0.70 (s, 3H), 0.05 (s, 6H).

[0148] Step 3. Synthesis of Intermediate C-3. To a solution of Intermediate C-2 (theoretical mass: 5.2 kg, 11.6 mol) in DCM (15 L) was added N-methylimidazole (1.37 L, 17.4 mol) and TEA (3.2 L, 23.2 mol) at 25 °C. TsCl (2.53 kg, 13.3 mol) was added portionwise to the solution while maintaining the internal temperature at 25-30 °C. The reaction mixture was stirred at 25 °C for 1 h. Water (10 L), citric acid (20%, 1 L), and HCl (1 M) were added to the mixture to adjust the pH to about 3. The organic layer was separated, washed with water (2×10 L), NaHCO (saturated aqueous solution 5 L) and brine (5 L), dried over NaSO, filtered and concentrated to give intermediate C-3 (6.63 kg, 95% for two steps) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 5.37-5.25 (m, 1H), 3.96 (dd, J = 2.8, 9.2 Hz, 1H), 3.79 (dd, J = 6.4, 9.2 Hz, 1H), 3.53-3.41 (m, 1H), 2.45 (s, 3H), 2.32-2.20 (m, 1H), 2.20-2.11 (m, 1H), 2.01-1.88 (m, 2H), 1.84-1.61 (m, 4H), 1.56-1.31 (m, 6H), 1.23-1.02 (m, 5H), 1.02-0.95 (m, 7H), 0.93-0.90 (m, 1H), 0.88 (s, 9H), 0.63 (s, 3H), 0.05 (s, 6H).

[0149] Step 4. Synthesis of Intermediate C-4. To a suspension of Intermediate C-3 (2.69 kg, 4.47 mol) in DMF (25 L) was added KI (1.48 g, 8.94 mol) at 70°C, and the mixture was stirred at 70°C for 1 hour. PhSO2Na (2.19 kg, 13.4 mol) was added, and stirring was continued at 70°C for 1 hour. The mixture was poured into water (50 L) and filtered. The filter cake was washed with water (2 x 10 L) to obtain a wet product, which was combined with two other batches from the previous synthesis. Half of this wet product was triturated with MeCN (20 L) at 80°C and cooled to 30°C. This heating and cooling process was repeated two more times, and the residue was collected by filtration and further triturated with MeCN / toluene (20 L, 10:1) at 80° C., filtered, washed with MeCN (3×5 L), and dried in vacuo to give Intermediate C-4 (2.21 kg) as a white solid. Another half of this wet product was triturated with MeCN (20 L) at 80° C. and cooled to 50° C. This heating and cooling process was repeated two more times, and the precipitate was collected by filtration to give Intermediate C-4 (1.92 kg) as an off-white solid. A total of 4.13 kg of product was obtained (yield 67%). 1 H NMR (400 MHz, CDCl3) δ 8.00-7.82 (m, 2H), 7.69-7.61 (m, 1H), 7.60-7.49 (m, 2H), 5.37-5.20 (m, 1H), 3.57-3.39 (m, 1H), 3.14 (d, J = 14.0 Hz, 1H), 2.85 (dd, J = 9.6, 14.0 Hz, 1H), 2.35-2.05 (m, 3H), 2.02-1.88 (m, 2H), 1.85-1.62 (m, 3H), 1.61-1.32 (m, 7H), 1.29-0.91 (m, 12H), 0.88 (s, 9H), 0.65 (s, 3H), 0.05 (s, 6H).

[0150] Step 5. Synthesis of Intermediate C-5. To a suspension of Intermediate C-4 (2.21 kg, 3.87 mol) in THF (10 L) was added TBAF.3H2O (1.87 kg, 5.92 mol). The mixture was heated and stirred at 65°C for 1 hour to give a clear solution, which was treated with water (25 L) and stirred at 80°C for 2 hours. After cooling, the mixture was filtered, and the filter cake was washed with water (3 x 10 L) and air-dried to give Intermediate C-5 (1.83 kg, crude) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 7.98-7.88 (m, 2H), 7.69-7.61 (m, 1H), 7.60-7.51 (m, 2H), 5.40-5.28 (m, 1H), 3.58-3.44 (m, 1H), 3.14 (d, J = 13.2 Hz, 1H), 2.85 (dd, J = 9.6, 14.0 Hz, 1H), 2.36-2.18 (m, 2H), 2.18-2.04 (m, 1H), 2.03-1.90 (m, 2H), 1.89-1.79 (m, 2H), 1.78-1.68 (m, 1H), 1.62-1.48 (m, 6H), 1.38-0.84 (m, 14H), 0.65 (s, 3H).

[0151] Step 6. Synthesis of Intermediate C-6. To a solution of Intermediate C-5 (50 g, 109 mmol) in THF (500 mL) was added Pd / C (wet, 10%, 11.7 g, 10.9 mmol) under Ar. After degassing with N three times, the reaction mixture was purged with H three times. The reaction mixture was stirred at 25 °C for 72 h under a hydrogen atmosphere (50 Psi). The formation of the desired product and consumption of the starting material were confirmed by NMR. The catalyst was removed by filtration, and the filtrate was concentrated to give Intermediate C-6 (39 g, crude) as an off-white solid, which was used directly in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.85-7.82 (m, 2H), 7.58-7.55 (m, 1H), 7.52-7.47 (m, 2H), 3.54-3.47 (m, 1H), 3.09-3.04 (m, 1H), 2.80-2.74 (m, 1H), 2.03-1.83 (m, 2H), 1.63-1.46 (m, 2H), 1.30-1.21 (m, 8H), 1.20-1.17 (m, 7H), 1.16-1.10 (m, 6H), 1.09-0.92 (m, 2H), 0.72 (s, 3H), 0.60-0.48 (m, 4H).

[0152] Step 7. Synthesis of Intermediate C-7. To a solution of Intermediate C-6 (196 g, 427 mmol) in DCM (2 L) was added PCC (137 g, 640 mmol), and the reaction mixture was stirred at 25° C. for 2 h, then filtered and concentrated in vacuo to give a residue that was purified by silica gel chromatography (DCM) to give Intermediate C-7 (145 g, 74%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 7.95-7.85 (m, 2H), 7.70-7.60 (m, 1H), 7.60-7.50 (m, 2H), 3.20-3.10 (m, 1H), 2.90-2.80 (m, 1H), 2.45-2.20 (m, 3H), 2.15-1.90 (m, 4H), 1.75-1.60 (m, 2H), 1.55-1.00 (m, 16H), 0.99 (s, 3H), 0.95-0.70 (m, 2H), 0.66 (s, 3H).

[0153] Step 8. Synthesis of Intermediate C-8. To a solution of BHT (499 g, 2.27 mmol) in anhydrous toluene (1 L) at 0° C. under N2, trimethylaluminum (2 M in toluene, 525 mL, 1.05 mmol) was added dropwise. The mixture was stirred at 25° C. for 1 hour and cooled to −70° C. Intermediate C-7 (160 g, 350 mmol) in toluene (500 mL) was added while maintaining the temperature below −60° C. The resulting mixture was stirred at −70° C. for 1 hour. Ethyl magnesium bromide (350 mL, 3.0 M in diethyl ether, 1.05 mmol) was added dropwise while maintaining the temperature below −60° C., and stirring was continued at −70° C. for an additional 1 hour. The reaction mixture was diluted with saturated citric acid. The mixture was quenched with acid (2 L) at −70° C., slowly warmed to 25° C., and extracted with ethyl acetate (500 mL × 3). The combined organic layers were washed with brine (200 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography (0% to 30% EtOAc in PE) to give intermediate C-8 (153 g, 90%) as an off-white solid. A small sample of this material (300 mg) was purified by recrystallization from MeCN (2 mL) to give intermediate C-8 (200 mg) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 7.95-7.85 (m, 2H), 7.70-7.60 (m, 1H), 7.60-7.50 (m, 2H), 3.20-3.10 (m, 1H), 2.90-2.80 (m, 1H), 2.15-2.05 (m, 1H), 1.95-1.85 (m, 1H), 1.75-1.60 (m, 3H), 1.55-1.40 (m, 6H), 1.40-1.15 (m, 11H), 1.15-0.95 (m, 7H), 0.88 (t, J = 7.2 Hz, 3H), 0.81 (s, 3H), 0.65-0.55 (m, 4H). LCMS 2.0 min chromatography Rt = 1.194 min, 30-90 AB, 100% purity, MS ESI C 30 H48 O4S[M+H2O] + Calculated value 504 and measured value 504.

[0154] Example 4. Synthesis of Compound 1. [ka] Step 1. Synthesis of Intermediate 1-2. To a suspension of Me3SI (3.93 g, 19.3 mmol) in THF (20 mL) was added a solution of t-BuOK (3.33 g, 29.8 mmol) in THF (10 mL) at 15 °C under N2, and the resulting suspension was stirred at 15 °C for 30 min. A solution of Intermediate 1-1 (2 g, 14.9 mmol) in THF (5 mL) was added dropwise at 15 °C, and the mixture was stirred at 15 °C for 16 h. The mixture was quenched with saturated NH4Cl (50 mL) and extracted with EtOAc (3 × 20 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated to give Intermediate 1-2 (1.8 g, 82%) as a brown solid. 1 H NMR (400 MHz, CDCl3) δ 2.72 (s, 2H), 2.20-1.85 (m, 8H).

[0155] Step 2. Synthesis of Intermediate 1-3. To a flask containing THF (5 mL) was added n-BuLi (2.5 M, 1.59 mmol, 0.636 mL) under N at −70° C. A suspension of A-6 (0.637 mmol, 300 mg) in THF (4 mL) was added dropwise to give a light yellow suspension. After stirring at −70° C. for 30 min, a solution of Intermediate 1-2 (0.764 mmol, 113 mg) in THF (1 mL) was added dropwise, and the reaction was stirred at 15° C. for 12 h. The reaction was quenched with saturated NH4Cl (30 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give Intermediate 1-3 (400 mg, crude) as a light yellow solid. , which was used directly in the next step.

[0156] Step 3. Synthesis of Compound 1. To a solution of intermediate 1-3 (400 mg, 0.646 mmol) in MeOH (5 mL) was added Mg powder (930 mg, 38.76 mmol) at 60 °C, and the mixture was stirred at 60 °C for 16 hours. The reaction was quenched with HCl (50 mL, 1 N) and extracted with DCM (2 × 30 mL). The combined organic phase was dried over NaSO, filtered, and concentrated, and the residue was purified by silica gel chromatography (0-10% EtOAc in PE) to give 50 mg of impure product, which was purified by SFC (column: AD (250 mm × 30 mm, 5 μm), gradient: 0-40% B (A = 0.05% NH / HO, B = MeOH); flow rate (mL / min): 60) to give compound 1 (32 mg, 10%) as an off-white solid. 1 H NMR (400 MHz, CDCl) δ 5.31-5.29 (m, 1H), 2.43-2.40 (m, 1H), 2.20-2.02 (m, 4H), 2.00-1.73 (m, 5H), 1.72-1.61 (m, 5H), 1.60-1.46 (m, 10H), 1.45-1.22 (m, 3H), 1.21-1.06 (m, 8H), 1.05-0.96 (m, 3H), 0.95-0.90 (m, 5H), 0.68 (s, 3H). LCMS 2.0 min chromatography showed Rt = 1.256 min, 30~90AB_ELSD, 100% purity, MS ESI C 30 H 45 F2[M+H-2H2O] + Calculated value: 443, measured value: 443.

[0157] Example 5. Synthesis of Compound 2. [ka] Step 1. Synthesis of Intermediate 2-2. To a solution of Me3SI (13.4 g, 66.1 mmol) in DMSO (100 mL) was added NaH (2.63 g, 66.1 mmol, 60%) portionwise at 0 °C. After stirring at 25 °C for 30 min, a solution of Intermediate 2-1 (5 g, 50.9 mmol) in 50 mL of DMSO was added dropwise, and the mixture was stirred at 25 °C for 1 h, poured into ice water (300 mL), and extracted with EtOAc (2 × 100 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EtOAc = 10 / 1) to give Intermediate 2-2 (0.6 g, 10%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 2.59 (s, 2H), 1.78-1.71 (m, 4H), 1.59-1.51 (m, 6H).

[0158] Step 2. Synthesis of Intermediate 2-3. To a flask containing THF (4 mL) at −70° C. under N was added n-BuLi (2.5 M, 3.17 mmol, 1.26 mL, 2.5 equiv.), followed by dropwise addition of a suspension of A-6 (600 mg, 1.27 mmol) in THF (6 mL). After stirring at −70° C. for 30 min, a solution of Intermediate 2-2 (227 mg, 2.03 mmol) was added. The reaction was stirred at 25° C. for 16 h, poured into ice water (100 mL), and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (30 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EtOAc=5 / 1) to give Intermediate 2-3 (400 mg, impure) as a light yellow solid. LCMS 1.5 min chromatography Rt = 1.066 min, 5-95 AB, MS ESI C 36 H 53 O3S [M+H-HO] + Calculated value 565, measured value 565.

[0159] Step 3. Synthesis of Compound 2. To a solution of intermediate 2-3 (400 mg, 0.69 mmol) in 10 mL of dry methanol, magnesium turnings (492 mg, 20.5 mmol) (activated with 0.5% aqueous HCl, water, dry ethanol, and MTBE) and NiCl (44.4 mg, 0.34 mmol) were added under N nitrogen, and the reaction was stirred at 50 °C for 1 h. The reaction was quenched at 10 °C by the dropwise addition of 2 M HCl (50 mL) until all solids were completely dissolved. The mixture was extracted with EtOAc (50 mL), and the organic layer was washed with saturated NaHCO (50 mL), brine (50 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography (PE / EtOAc = 10 / 1) to give compound 2 (42 mg, 14%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 5.31-5.30 (m, 1H), 2.44-2.41 (m, 1H), 2.02-1.93 (m, 3H), 1.86-1.58 (m, 6H), 1.52-1.36 (m, 16H), 1.32-1.25 (m, 3H), 1.18-1.07 (m, 9H), 1.03-0.92 (m, 8H), 0.68 (s, 3H). LCMS: Rt = 1.353 min, 30-90 AB, MS ESI C. 30 H 47 [M+H-2H2O] + Calculated value 407, measured value 407.

[0160] Example 6. Synthesis of Compound 3. [ka] Step 1. Synthesis of Intermediate 3-2. To a mixture of trimethylsulfoxonium iodide (47.1 g, 231 mmol) in 100 mL of DMSO, NaH (9.23 g, 60% in mineral oil, 231 mmol) was added portionwise at 10 °C under N. The mixture was stirred at 10 °C for 30 min. Intermediate 3-1 (15 g, 178 mmol) in DMSO (50 mL) was added dropwise below 15 °C, and the reaction mixture was stirred at 15 °C for 20 h. The reaction was quenched with water (200 mL) at 10 °C and extracted with MTBE (2 × 300 mL). The combined organic phase was washed with water (2×400 mL), brine (200 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue which was purified by silica gel chromatography (DCM) to give intermediate 3-2 (11 g, impure) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 2.83 (s, 2H), 1.95-1.77 (m, 4H), 1.74-1.60 (m, 4H).

[0161] Step 2. Synthesis of Intermediate 3-3. To a flask containing THF (4 mL) at −70° C. under N was added n-BuLi (2.5 M, 5.30 mmol, 2.11 mL), followed by dropwise addition of a suspension of A-6 (2.12 mmol, 1 g) in THF (10 mL). After stirring at −70° C. for 30 minutes, a solution of Intermediate 3-2 (4.24 mmol, 416 mg) in THF (4 mL) was added, and the reaction was stirred at −70° C. for 10 minutes and at 25° C. for 16 hours. The reaction was quenched with water (10 mL) and extracted with EtOAc (3×50 mL). The combined organic phase was washed with brine (100 mL), dried over NaSO, filtered, and concentrated in vacuo to give Intermediate 3-3 (1.2 g, crude) as a yellow solid. LCMS 2.0 min chromatography Rt = 1.161 min and 1.222 min, 30–90 AB, 28%, MS ESI C 35 H 52 O4SNa [M+Na] + Calculated value: 591, measured value: 591.

[0162] Step 3. Synthesis of Compound 3. To a solution of intermediate 3-3 (1.2 g, 2.10 mmol) in 50 mL of dry MeOH and 25 mL of THF, magnesium turnings (3.06 g, 126 mol) (activated with 0.5% aqueous HCl, water, dry ethanol, and MTBE) and NiCl (54.4 mg, 0.42 mmol) were added under N at 50 °C to initiate continuous hydrogen evolution. The reaction was quenched at 10 °C by adding 1 M HCl (200 mL) until all solids were completely dissolved. The mixture was extracted with EtOAc (2 × 200 mL). The combined organic layer was washed with saturated NaHCO (500 mL), brine (500 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give compound 3 (600 mg, crude), which was purified by column chromatography on silica gel (PE / EtOAc = 5 / 1) to give the product (150 mg, impure) as an off-white solid. The impure product was purified by SFC (column: AD (250 mm × 30 mm, 5 μm); conditions: base-ETOH, 40% B; flow rate (ml / min): 60 mL / min) to give 30 mg of product. The product was washed with n-hexane (5 mL) to give compound 3 (3 mg, 0.3%). 1 H NMR (400 MHz, CDCl3) δ 5.34-5.28 (m, 1H), 2.46-2.35 (m, 1H), 2.05-1.93 (m, 3H), 1.89-1.59 (m, 12H), 1.53-1.24 (m, 11H), 1.21-0.99 (m, 13H), 0.96-0.89 (m, 4H), 0.68 (s, 3H). LCMS 2.0 min chromatography Rt = 1.161 min and 1.295 min, 30-90 AB_E, MS ESI C 29 H 45 [M+H-2H2O] + Calculated value: 393, measured value: 393.

[0163] Example 7. Synthesis of Compound 4. [ka] Step 1. Synthesis of intermediate 4-2. To a solution of intermediate 4-1 (1 g, 14.6 mmol) in DCM (30 mL) was added m-CPBA (3.77 g, 21.9 mmol), and the mixture was stirred at 25° C. for 16 hours. The reaction mixture was filtered, and the filtrate was distilled under reduced pressure to obtain a solution of intermediate 4-2 in DCM. The solution was distilled under standard pressure to obtain a solution of intermediate 4-2 (5 g, 1 A 2% solution in DCM was obtained as calculated from 1HNMR, 8% yield as calculated from 1HNMR. 1 H NMR (400 MHz, CDCl3) δ 2.67 (s, 2H), 2.54-2.43 (m, 2H), 2.30-2.20 (m, 2H), 1.89-1.72 (m, 2H).

[0164] Step 2. Synthesis of Intermediate 4-3. To a solution of n-BuLi (2.5 M in hexane, 1.1 mL, 2.65 mmol) in anhydrous THF (8 mL) under nitrogen at −78° C., A-6 (500 mg, 1.06 mmol) was added in one portion, and the mixture was stirred at −78° C. for 0.5 h. A solution of Intermediate 4-2 (5 g, 2% in DCM, 1.18 mmol) was added dropwise to the mixture, and the reaction was gradually warmed to 15° C. After stirring for 16 h, the reaction was quenched with saturated NH4Cl (20 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (PE:EtOAc = 9:1) to give Intermediate 4-3 (100 mg, 17%) as an off-white solid. LCMS 2.0 min chromatography Rt = 1.131 min, 30-90 AB, MS ESI C 34 H 49 O3S [M+H-H2O] + Calculated value 537, measured value 537.

[0165] Step 3. Synthesis of Compound 4. To a solution of intermediate 4-3 (100 mg, 0.180 mmol) in anhydrous MeOH (5 mL) was added magnesium powder (260 mg, 10.7 mmol) under nitrogen. The mixture was stirred at 60 °C for 2 hours, cooled to room temperature, neutralized with 1 M HCl, and extracted with EtOAc (4 × 20 mL). The combined organic layer was washed with water (40 mL) and brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (PE: EtOAc = 10:1) to give a residue that was triturated with n-hexane to give compound 4 (23 mg, 31%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 5.34-5.26 (m, 1H), 2.46-2.37 (m, 1H), 2.09-1.57 (m, 14H), 1.54-1.23 (m, 11H), 1.21-1.05 (m, 8H), 1.04-0.90 (m, 8H), 0.69 (s, 3H). LCMS 2.0 min chromatography Rt = 1.230 min, 30-90 AB, MS ESI C 28 H 43 [M+H-2H2O] + Calculated value: 379, measured value: 379.

[0166] Example 8. Synthesis of Compound 5. [ka] Step 1. Synthesis of Intermediate 5-2. To a mixture of trimethylsulfoxonium iodide (28.3 g, 139 mmol) in DMSO (60 mL) was added NaH (5.55 g, 60% in mineral oil, 139 mmol) in portions at 5 °C under N2, and the mixture was stirred at 5 °C for 30 min. Dihydrofuran-3(2H)-one (10 g, 116 mmol) in DMSO (40 mL) was added dropwise while maintaining the temperature below 15 °C, and the resulting mixture was stirred at 15 °C for 20 h. The reaction was quenched with water (200 mL) at 10 °C and extracted with MTBE (2 × 200 mL). The combined organic phase was washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated, and the residue was purified by silica gel chromatography (0% to 40% EtOAc in PE) to give intermediate 5-2 (100 mg, 1%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 4.12-3.93 (m, 3H), 3.68 (d, J = 10.4Hz, 1H), 3.05 (d, J = 4.4Hz, 1H), 2.96 (d, J = 4.4Hz, 1H), 2.37-2.25 (m, 1H), 2.02-1.92 (m, 1H).

[0167] Step 2. Synthesis of intermediate 5-3. To a flask containing THF (2 mL) under N2 at -78 °C, n-BuLi (0.9 mL, 2.22 mmol, 2.5 M) was added, followed by A- A suspension of 6 (300 mg, 0.637 mmol) in THF (4 mL) was added to give a light yellow suspension. After stirring at −78° C. for 30 min, a solution of intermediate 5-2 (100 mg, 1.01 mmol) in THF (2 mL) was added, and the reaction was stirred at −78° C. for 10 min and at 15° C. for 16 h. The reaction was quenched with saturated NH4Cl (20 mL), extracted with EtOAc (3×20 mL), and the combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to give crude intermediate 5-3 (300 mg) as a yellow solid, which was used directly in the next step. LCMS 1.5 min chromatography: Rt = 0.907 min, 5-95 AB, MS ESI C 34 H 49 O4S [M+H-H2O] + Calculated value 553, measured value 553.

[0168] Step 3. Synthesis of Compound 5. To a solution of intermediate 5-3 (300 mg, 0.525 mmol) in 20 mL of dry MeOH under N2, magnesium turnings (127 mg, 5.24 mmol) (activated with 0.5% aqueous HCl, water, dry EtOH, and MTBE) and NiCl2 (13.6 mg, 0.10 mmol) were added with stirring at 55 °C to initiate continuous hydrogen evolution. After adding four batches of 127 mg of magnesium turnings, most of the starting material was consumed. The reaction was quenched by adding 2 M HCl (50 mL) until all solids were completely dissolved. The mixture was extracted with DCM (3 × 20 mL), and the combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0% to 50% EtOAc in PE) to give compound 5 (34 mg, 15%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 5.37-5.24 (m, 1H), 4.08-3.98 (m, 1H), 3.94-3.84 (m, 1H), 3.74-3.65 (m, 1H), 3.59-3.51 (m, 1H), 2.48-2.37 (m, 1H), 2.06-1.67 (m, 9H), 1.66-1.38 (m, 13H), 1.34-1.07 (m, 8H), 1.06-0.90 (m, 7H), 0.68 (s, 3H). LCMS: Rt = 1.111 min, 30-90 AB_E, MS ESI C. 30 H 49 O3NNa [M+MeCN+Na] + Calculated value: 494, measured value: 494.

[0169] Example 9. Preparation of Compounds 5-A and 5-B [ka] Racemic compound 5 (1.4 g) was purified by SFC (column: AD (250 mm × 30 mm, 5 μm)); conditions: 0.1% NH₃HO in IPA; gradient 40% B; gradient time (min): 30; flow rate (ml / min): 60) to give compound 5-A (350 mg, 15%) as an off-white solid and compound 5-B (310 mg, 14%) as an off-white solid.

[0170] Compound 5-A 1 H NMR (400 MHz, CDCl3) δ 5.33-5.28 (m, 1H), 4.10-4.00 (m, 1H), 3.93-3.85 (m, 1H), 3.69 (d, J = 9.2 Hz, 1H), 3.54 (d, J = 9.2 Hz, 1H), 2.46-2.38 (m, 1H), 2.04-1.88 (m, 5H), 1.87-1.56 (m, 9H), 1.53-1.23 (m, 7H), 1.21-1.09 (m, 7H), 1.08-0.89 (m, 9H), 0.68 (s, 3H). LCMS 2 min chromatography Rt = 1.091 min, 30-90AB_E, 100% purity, MS ESI C 28 H 46 O3Na [M+Na] + Calculated value: 453, measured value: 453.

[0171] Compound 5-B 1 H NMR (400 MHz, CDCl3) δ 5.32-5.28 (m, 1H), 4.10-4.00 (m, 1H), 3.93-3.85 (m, 1H), 3.70 (d, J = 9.2 Hz, 1H), 3.55 (d, J = 9.2 Hz, 1H), 2.45-2.39 (m, 1H), 2.04-1.83 (m, 6H), 1.81-1.63 (m, 4H), 1.61-1.54 (m, 5H), 1.52-1.37 (m, 6H), 1.26-1.08 (m, 8H), 1.05-0.92 (m, 8H), 0.68 (s, 3H). LCMS 2 min chromatography Rt = 1.093 min, 30-90AB_E, 100% purity, MS ESI C 28 H 43 O [M+H-2H2O] + Calculated value: 395, measured value: 395.

[0172] Example 10. Synthesis of Compound 6. [ka] Step 1. Synthesis of Intermediate 6-2. To a mixture of trimethylsulfoxonium iodide (12.2 g, 59.8 mmol) in DMSO (40 mL) at 5 °C under N was added NaH (2.38 g, 60% in mineral oil, 59.8 mmol) in portions, and the mixture was stirred at 5 °C for 30 min. Intermediate 6-1 (5 g, 49.9 mmol) in DMSO (40 mL) was added dropwise while maintaining the temperature below 15 °C, and the reaction mixture was stirred at 15 °C for 20 h. The reaction was quenched with water (200 mL) at 10 °C and extracted with MTBE (2 × 200 mL). The combined organic phase was washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated, and the resulting residue was purified by silica gel chromatography (0% to 50% EtOAc in PE) to give intermediate 6-2 (1.5 g, 26%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 3.93-3.76 (m, 4H), 2.69 (s, 2H), 1.94-1.81 (m, 2H), 1.58-1.48 (m, 2H).

[0173] Step 2. Synthesis of Intermediate 6-3. To a flask containing THF (5 mL) at −78° C. under N was added n-BuLi (2.96 mL, 7.42 mmol, 2.5 M), followed by dropwise addition of a suspension of A-6 (1 g, 2.12 mmol) in THF (10 mL) to give a light yellow suspension. After stirring at −78° C. for 30 min, a solution of Intermediate 6-2 (483 mg, 4.24 mmol) in THF (5 mL) was added, and the reaction was stirred at −78° C. for 10 min and at 15° C. for 16 h. The reaction was quenched with saturated NH4Cl (50 mL) and extracted with EtOAc (3×30 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. Intermediate 6-3 (1 g) was obtained as a yellow solid, which was used directly in the next step. LCMS 3.0 min chromatography, Rt = 2.423 min, 10-80 AB, MS ESI C 35 H52 O5SNa [M+Na] + Calculated value 607, measured value 607.

[0174] Step 3. Synthesis of Compound 6. To a solution of intermediate 6-3 (1 g, 1.70 mmol) in 20 mL of anhydrous MeOH under N2, magnesium turnings (410 mg, 16.9 mmol) (activated with 0.5% aqueous HCl, water, absolute ethanol, and MTBE) and NiCl2 (44.0 mg, 0.34 mmol) were added with stirring at 55 °C to initiate continuous hydrogen evolution. After adding four batches of magnesium turnings (410 mg total), the reaction was quenched at 10 °C by dropwise addition of 2 M HCl (80 mL) until all solids were completely dissolved. The mixture was extracted with DCM (3 × 50 mL), and the combined organic phase was washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (0% to 70% EtOAc in PE) to give compound 6 (200 mg, 26%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 5.24-5.15 (m, 1H), 4.34 (s, 1H), 4.02 (s, 1H), 3.64-3.47 (m, 4H), 2.30-2.23 (m, 1H), 2.00-1.75 (m, 5H), 1.70-1.24 (m, 14H), 1.20-0.83 (m, 18H), 0.63 (s, 3H). LCMS 3.0 minutes Chromatography: Rt = 2.043 min, 10-80 AB, MS ESI C 29 H 45 O [M+H-2H2O] + Calculated value 409, measured value 409.

[0175] Example 11. Synthesis of Compound 7. [ka] Step 1. Synthesis of Intermediate 7-2. To a solution of trimethylsulfoxonium iodide (26.5 g, 130 mmol) in 50 mL of DMSO at 10 °C under N was added NaH (5.18 g, 60% in mineral oil, 130 mmol) in portions, and the mixture was stirred at 10 °C for 30 min. Intermediate 7-1 (20 g, 100 mmol) in DMSO (50 mL) was added dropwise while maintaining the temperature below 15 °C, and stirring was continued at 15 °C for 20 h. The reaction was quenched with water (200 mL) at 10 °C and extracted with MTBE (2 × 300 mL). The combined organic phase was washed with water (2×400 mL), brine (200 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue, which was purified by silica gel chromatography (PE: EtOAc = 6:1) to give intermediate 7-2 (15 g, 70%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 3.77-3.66 (m, 2H), 3.43 (m, 2H), 2.69 (s, 2H), 1.86-1.72 (m, 2H), 1.52-1.39 (m, 11H).

[0176] Step 2. Synthesis of Intermediate 7-3. To a solution of n-BuLi (2.5 M in hexane, 4.2 mL, 10.6 mmol) in anhydrous THF (20 mL) at −70° C. under nitrogen, A-6 (2 g, 4.24 mmol) was added in one portion, and the mixture was stirred at −70° C. for 30 min. Intermediate 7-2 (1.80 g, 8.48 mmol) was added, and the resulting mixture was gradually warmed to 15° C. and stirred for an additional 16 h. The reaction was quenched with saturated NH4Cl (30 mL) and extracted with EtOAc (3 × 40 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (PE:THF = 5:1) to give Intermediate 7-3 (2.3 g, 79%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.96-7.87 (m, 2H), 7.72-7.55 (m, 3H), 5.31-5.24 (m, 1H), 4.00-3.83 (m, 2H), 3.43-3.32 (m, 1H), 3.30-3.06 (m, 2H), 2.44-2.24 (m, 2H), 1.99-1.87 (m, 3H), 1.80-1.50 (m, 11H), 1.49-1.42 (m, 12H), 1.40-1.25 (m, 4H), 1.18-0.80 (m, 15H), 0.43 (s, 3H).

[0177] Step 3. Synthesis of Intermediate 7-4. To a solution of intermediate 7-3 (2.3 g, 3.36 mmol) and nickel(II) chloride (435 mg, 3.36 mmol) in anhydrous MeOH (30 mL) and THF (10 mL) under nitrogen at 45 °C, one portion of magnesium turnings (3.25 g, 134 mmol) was added. The internal temperature rose to 60 °C, and vigorous gas evolution was observed. The mixture was stirred at 60 °C for 3 h, cooled to room temperature, quenched with 1 M HCl (100 mL), and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with saturated NaHCO (100 mL) and brine (100 mL), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography on silica gel (PE:THF=6:1) to give intermediate 7-4 (1.1 g, 60%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 5.34-5.27 (m, 1H), 3.91-3.66 (m, 2H), 3.23-3.07 (m, 2H), 2.47-2.38 (m, 1H), 2.03-1.91 (m, 3H), 1.88-1.65 (m, 4H), 1.60-1.54 (m, 4H), 1.47-1.42 (m, 12H), 1.38-1.24 (m, 4H), 1.20-0.97 (m, 14H), 0.97-0.77 (m, 7H), 0.68 (s, 3H).

[0178] Step 4. Synthesis of Compound 7. To a solution of intermediate 7-4 (1 g, 1.83 mmol) in EtOAc (8 mL) and DCM (8 mL) was added ethanol (843 mg, 18.3 mmol) and acetyl chloride (1.43 g, 18.3 mmol). The mixture was stirred at 15 °C for 16 hours. The precipitated solid was collected by filtration and dried in vacuo to give the crude product (720 mg), which was triturated with methanol to give the hydrochloride salt of compound 7 (260 mg, 30%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.70-8.38 (m, 1H), 5.24-5.15 (m, 1H), 4.52-4.24 (m, 2H), 3.11-2.94 (m, 4H), 2.35-2.25 (m, 1H), 1.98-1.77 (m, 4H), 1.71-1.50 (m, 8H), 1.47-1.31 (m, 7H), 1.28-0.98 (m, 8H), 0.97-0.86 (m, 10H), 0.65 (s, 3H). LCMS 2.0 min chromatography gave Rt = 1.054 min, 10~80 AB, MS ESI C 29 H 50 NO2[M+H] + Calculated value: 444, measured value: 444.

[0179] Example 12. Synthesis of Compound 8. [ka] To a suspension of compound 7 hydrochloride (50 mg, 0.104 mmol) in DCE (4 mL) was added EtN (21.0 mg, 0.208 mmol), paraformaldehyde (18.7 mg, 0.208 mmol), and NaBHCN (16.3 mg, 0.260 mmol), and the mixture was stirred at 25 °C for 16 h. The reaction mixture was neutralized with 1 M HCl and purified by preparative HPLC (column: DuraShell 150 × 25 mm × 5 μm. Mobile phase: A: water (0.1% TFA), B: ACN. Gradient: 35–60% B over 25 min. Flow rate: 30 mL / min) to give compound 8 (3 mg, 6%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 5.34-5.26 (m, 1H), 3.44-3.32 (m, 2H), 3.19-3.04 (m, 2H), 2.78 (d, J = 4.0 Hz, 3H), 2.48-2.37 (m, 1H), 2.16-1.92 (m, 5H), 1.86-1.56 (m, 9H), 1.51-1.35 (m, 7H), 1.31-1.04 (m, 10H), 1.04-0.87 (m, 8H), 0.67 (s, 3H). LCMS 2.0 min chromatography Rt = 0.748 min, 30~90 AB, MS ESI C 30 H 52 NO2[M+H] + Calculated value: 458, measured value: 458.

[0180] Example 13. Synthesis of Compound 9. [ka] To a suspension of compound 7 hydrochloride (50 mg, 0.104 mmol) in DCM (4 mL) was added EtN (31.5 mg, 0.312 mmol) and AcCl (16.3 mg, 0.208 mmol), and the mixture was stirred at 25 °C for 16 h. The reaction mixture was neutralized with 1 M HCl and purified by preparative HPLC (column: DuraShell 150 × 25 mm × 5 μm. Mobile phase: A: water (0.1% TFA), B: ACN. Gradient: 51–76% B in 25 min. Flow rate: 30 mL / min) to give compound 9 (15 mg, 30%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 5.35-5.25 (m, 1H), 4.43-4.27 (m, 1H), 3.65-3.38 (m, 2H), 3.12-2.94 (m, 1H), 2.48-2.37 (m, 1H), 2.11 (s, 11H), 1.89-1.57 (m, 6H), 1.52-1.21 (m, 9H), 1.20-1.03 (m, 8H), 1.03-0.89 (m, 8H), 0.68 (s, 3H). LCMS 2.0 min chromatography Rt = 1.036 min, 30-90 AB, MS ESI C 31 H 52 NO3[M+H] + Calculated value: 486, measured value: 486.

[0181] Example 14. Synthesis of Compound 10. [ka] Step 1. Synthesis of Intermediate 10-2. To a suspension of t-BuOK (3.53 g, 31.6 mmol) in THF (30 mL) was added MeSI (4.18 g, 20.5 mmol) under N, and the suspension was stirred at 15 °C for 30 min. A solution of Intermediate 10-1 (2 g, 15.8 mmol) in 10 mL of THF was added dropwise, and stirring was continued at 15 °C for 16 h. The reaction was quenched with saturated NH Cl (100 mL) and extracted with EtOAc (3 × 150 mL). The combined organic phase was dried over Na SO , filtered, and concentrated in vacuo to give Intermediate 10-2 (1.8 g, 81%) as a yellow liquid. 1 H NMR (400 MHz, CDCl3) δ 2.58 (s, 2H), 1.90-1.80 (m, 1H), 1.70-1.55 (m, 2H), 1.54-1.45 (m, 3H), 1.40-1.30 (m, 2H), 1.00-0.90 (m, 6H).

[0182] Step 2. Synthesis of Intermediate 10-3. To a flask containing THF (0.5 mL) under N2 at -70 °C, n-BuLi (1.05 mL, 2.5 M, 2.65 mmol) was added, followed by dropwise addition of a suspension of Intermediate A-6 (500 mg, 1.06 mmol) in THF (1 mL) to give a light yellow suspension. After stirring at -70 °C for 30 min, a solution of Intermediate 10-2 (178 mg, 1.27 mmol) in THF (1 mL) was added dropwise, and the reaction was stirred at 15 °C for 12 h. The reaction was quenched with saturated NH4Cl (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give Intermediate 10-3 (500 mg, crude) as a yellow solid, which was used directly in the next step.

[0183] Step 3. Synthesis of Compound 10. To a solution of intermediate 10-3 (500 mg, 0.818 mmol) and nickel(II) chloride (26.4 mg, 0.204 mmol) in dry methanol (20 mL) under N was added magnesium powder (794 mg, 32.7 mmol) with stirring at 50 °C to initiate continuous hydrogen evolution. After stirring at 60 °C for 1 h, the reaction was quenched at 10 °C by the dropwise addition of 2 M HCl (100 mL) until all solids were completely dissolved. After extraction with EtOAc (2 × 150 mL), the combined organic layers were washed with saturated aqueous NaHCO (300 mL), brine (300 mL), dried over NaSO, filtered, and concentrated in vacuo to give a yellow solid, which was purified by silica gel chromatography (PE / THF = 4 / 1) to give 150 mg of a white solid. 72 mg of this solid was purified by SFC (column: AD (250 mm × 30 mm, 10 μm)), gradient: 55–55% B (A = 0.1% NH3 / HO, B = EtOH), flow rate: 80 mL / min) to give compound 10 (39 mg) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 5.35-5.30 (m, 1H), 2.45-2.40 (m, 2H), 2.10-1.95 (m, 3H), 1.90-1.65 (m, 7H), 1.60-1.40 (m, 14H), 1.39-1.10 (m, 11H), 1.09-1.00 (m, 4H), 0.09-0.88 (m, 6H), 0.87 (s, 3H), 0.67 (m, 3H). LCMS 2.0 min chromatography Rt = 1.481 min, 30-90 AB, 100% purity, MS ESI C 32 H 51 [M+H-2H2O] - Calculated value: 435, measured value: 435.

[0184] Example 15. Synthesis of Compound 11. [ka] Step 1. Synthesis of Intermediate 11-2. To a mixture of trimethylsulfoxonium iodide (12.2 g, 59.8 mmol) in DMSO (40 mL) was added NaH (2.38 g, 60% in mineral oil, 59.8 mmol) in portions at 5 °C under N 2 , and the mixture was stirred at 5 °C for 30 min. Intermediate 11-1 (5 g, 49.9 mmol) in DMSO (40 mL) was added dropwise while maintaining the temperature below 15 °C, and stirring was continued at 15 °C for 20 h. The reaction was quenched with water (200 mL) at 10 °C and extracted with DCM (2 × 200 mL). The combined organic phase was washed with brine (200 mL), dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by silica gel chromatography (0% to 50% EtOAc in PE) to give intermediate 11-2 (2 g, 35%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 3.81-3.60 (m, 3H), 3.49 (d, J = 12.0 Hz, 1H), 2.73-2.65 (m, 2H), 2.03-1.82 (m, 2H), 1.81-1.62 (m, 2H).

[0185] Step 2. Synthesis of Intermediate 11-3. To a flask containing THF (3 mL) at −78° C. under N was added n-BuLi (1.48 mL, 3.71 mmol, 2.5 M), followed by dropwise addition of a suspension of Intermediate A-6 (500 mg, 1.06 mmol) in THF (5 mL), resulting in a light yellow suspension. After stirring at −78° C. for 30 minutes, a solution of Intermediate 11-2 (362 mg, 3.18 mmol) in THF (2 mL) was added, and the reaction was stirred at −78° C. for 10 minutes and at 15° C. for 16 hours. The reaction was quenched with aqueous NH4Cl (50 mL) and extracted with EtOAc (3×30 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude intermediate 11-3 (500 mg) as a yellow solid, which was used directly in the next step. LCMS 1.5 min chromatography Rt = 0.939 min, 5-95 AB, purity 79%, MS ESI C35 H 51 04S [M+H -H2O] + Calculated value: 567, measured value: 567.

[0186] Step 3. Synthesis of Compound 11. To a solution of intermediate 11-3 (500 mg, 0.85 mmol) in 20 mL of dry MeOH under N2, magnesium turnings (828 mg, 34.1 mmol) (activated with 0.5% aqueous HCl, water, dry ethanol, and MTBE) and NiCl2 (22 mg, 0.17 mmol) were added with stirring at 55 °C to initiate continuous hydrogen evolution. After adding two batches of magnesium turnings (828 mg), most of the starting material was consumed. The reaction mixture was quenched at 10 °C by adding 2 M HCl (40 mL) until all solids were completely dissolved. The resulting solution was extracted with DCM (3 × 50 mL), and the combined organic phase was washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (0% to 20% MeOH in DCM) to give the crude product, which was recrystallized from MeCN (20 mL) to give compound 11 (150 mg, 40%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 5.25-5.22 (m, 1H), 3.84-3.75 (m, 1H), 3.50-3.40 (m, 1H), 3.36-3.21 (m, 2H), 2.39-2.32 (m, 1H), 2.19-2.14 (m, 1H), 1.96-1.86 (m, 3H), 1.85-1.51 (m, 6H), 1.49-1.40 (m, 3H), 1.44-1.26 (m, 8H), 1.25-1.14 (m, 2H), 1.13-0.97 (m, 8H), 0.96-0.82 (m, 8H), 0.61 (s, 3H). LCMS 2 min chromatography Rt = 1.226 min, 30-90AB_E, 100% purity, MS ESI C 29 H 45 O [M+H-2H2O] +Calculated value 409, measured value 409.

[0187] Example 16. Synthesis of Compound 12. [ka] Step 1. Synthesis of Intermediate 12-1. To a flask containing THF (5 mL), BuLi (4.12 mL, 2.5 M in hexane, 10.3 mmol) was added, and the solution was cooled to −70° C. and treated with a solution of Intermediate B-4 (2 g, 4.12 mmol) in THF (10 mL). The mixture was stirred at −70° C. for 1 h and treated with a solution of Intermediate 1-2 (1.89 g, 6.18 mmol, 50% purity) in THF (5 mL) at −70° C. The reaction was warmed to 25° C. and stirred for 16 h. NH4Cl (40 mL, saturated aqueous solution) was added, and the mixture was extracted with EtOAc (30 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-25% EtOAc in PE) to give intermediate 12-1 (150 mg, 6%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 7.96-7.90 (m, 2H), 7.70-7.62 (m, 1H), 7.62-7.55 (m, 2H), 5.30-5.26 (m, 1H), 3.58 (m, 1H), 2.40-2.28 (m, 3H), 2.10-2.00 (m, 2H), 1.99-1.76 (m, 6H), 1.75-1.58 (m, 7H), 1.56-1.31 (m, 8H), 1.30-1.15 (m, 4H), 1.14-1.03 (m, 3H), 1.01 (s, 3H), 0.96-0.75 (m, 8H), 0.58 (s, 3H).

[0188] Step 2. Synthesis of Compound 12. To a solution of intermediate 12-1 (170 mg, 0.268 mmol) in MeOH (15 mL) was added Mg powder (256 mg, 10.7 mmol) at 55° C. After stirring at 60° C. for 16 h, the reaction was quenched by adding HCl (50 mL, 1N) until the reaction became clear, and the resulting solution was diluted with DCM. (2×30 mL). The combined organic phases were dried over NaSO, filtered, concentrated, and purified by silica gel chromatography (0-10% EtOAc in PE) to give compound 12 (50 mg, 38%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 5.30-5.26 (m, 1H), 2.38-2.31 (m, 1H), 2.18-1.76 (m, 8H), 1.75-1.58 (m, 8H), 1.56-1.41 (m, 9H), 1.40-1.20 (m, 3H), 1.18-1.05 (m, 5H), 1.02 (s, 3H), 1.00-0.90 (m, 6H), 0.88-0.80 (m, 3H), 0.68 (s, 3H). LCMS 2.0 min chromatography Rt = 1.268 min, 30-90 AB, 100% purity, MS ESI C 31 H 47 F2[M+H-2H2O] + Calculated value: 457, measured value: 457.

[0189] Example 17. Synthesis of Compound 13. [ka] Step 1. Synthesis of Intermediate 13-1. To a solution of diisopropylamine (526 mg, 5.20 mmol) in THF (1 mL) was added n-BuLi (1.93 mL, 2.5 M in hexane, 4.84 mmol) at −70° C. under N, and the mixture was warmed to 25° C. After cooling to −70° C., a suspension of Intermediate B-4 (588 mg, 1.21 mmol) in THF (5 mL) was added dropwise under N, and stirring was continued at −70° C. for 30 min. Intermediate 10-2 (339 mg, 2.42 mmol) was added at −70° C., and the reaction was slowly warmed to 25° C. After stirring for 16 h, the reaction was quenched with saturated aqueous NHCl (15 mL), and the resulting mixture was extracted with EtOAc (2×15 mL). The combined organic phase was washed with brine (2×20 mL), dried over Na 2 SO 4 , filtered, and concentrated in vacuo to afford intermediate 13-1 (840 mg, crude) as a yellow oil, which was used directly in the next step without further purification.

[0190] Step 2. Synthesis of Compound 13. A solution of intermediate 13-1 (840 mg, 1.34 mmol) in MeOH (40 mL) was heated to 65 °C. NiCl (34.2 mg, 268 μmol) and Mg powder (1.28 g, 53.6 mmol) were added in one portion, and the mixture was stirred at 65 °C for 1 h. After cooling, the mixture was quenched by adding HCl (40 mL, 2 N) until the reaction became clear, and the resulting solution was extracted with DCM (2 × 40 mL). The combined organic layers were dried over NaSO, filtered, concentrated, and purified by silica gel chromatography (0–10% EtOAc in PE) to give compound 13 (240 mg, 37%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 5.31-5.26 (m, 1H), 2.42-2.31 (m, 1H), 2.07-1.92 (m, 3H), 1.92-1.78 (m, 1H), 1.77-1.68 (m, 1H), 1.68-1.58 (m, 3H), 1.52-1.44 (m, 10H), 1.44-1.34 (m, 4H), 1.34-1.23 (m, 3H), 1.22-1.14 (m, 3H), 1.14-1.05 (m, 5H), 1.04-0.96 (m, 5H), 0.96-0.89 (m, 7H), 0.89-0.82 (m, 6H), 0.68 (s, 3H). LCMS 2 min chromatography Rt = 1.475 min, 30-90AB, 100% purity, MS ESI C 33 H 53 [M+H-2H2O] + Calculated value: 449, measured value: 449.

[0191] Example 18. Synthesis of Compound 14. [ka] Step 1. Synthesis of Intermediate 14-1. To a flask containing THF (3 mL) at −78° C. under N was added n-BuLi (1.44 mL, 3.60 mmol, 2.5 M), followed by dropwise addition of a suspension of Intermediate B-4 (500 mg, 1.03 mmol) in THF (5 mL), resulting in a light yellow suspension. After stirring at −78° C. for 30 minutes, a solution of Intermediate 6-2 (352 mg, 3.09 mmol) in THF (2 mL) was added, and the reaction was stirred at −78° C. for 10 minutes and at 15° C. for 16 hours. The reaction was quenched with saturated NH4Cl (50 mL) and extracted with DCM (3×50 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude intermediate 14-1 (500 mg) as a yellow solid, which was used directly in the next step. LCMS 1.5 min chromatography Rt = 0.953 min, 5-95 AB, purity 36%, MS ESI C36 H 54 O5SNa [M+Na] + Calculated value 621, measured value 621.

[0192] Step 2. Synthesis of Compound 14. To a solution of intermediate 14-1 (500 mg, 0.834 mmol) in 20 mL of anhydrous MeOH under N2, magnesium turnings (809 mg, 33.3 mmol) (activated with 0.5% aqueous HCl, water, anhydrous EtOH, and MTBE) and NiCl2 (21.5 mg, 0.17 mmol) were added with stirring at 55 °C to initiate continuous hydrogen evolution. After adding two batches of 809 mg of magnesium turnings, most of the starting material was consumed. The reaction mixture was quenched at 10 °C by adding 2 M HCl (40 mL) until all solids were completely dissolved, and the resulting solution was extracted with DCM (3 × 50 mL). The combined organic phase was washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (0% to 20% MeOH in DCM) to give the crude product, which was recrystallized from MeCN (20 mL) to give compound 14 (150 mg, 39%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 5.26-5.18 (m, 1H), 3.78-3.61 (m, 4H), 2.34-2.25 (m, 1H), 2.02-1.85 (m, 4H), 1.83-1.71 (m, 1H), 1.69-1.49 (m, 7H), 1.47-1.35 (m, 9H), 1.27-1.15 (m, 4H), 1.12-0.96 (m, 9H), 0.90-0.77 (m, 7H), 0.61 (s, 3H). LCMS 2.0 min chromatography Rt = 1.227 min, 30-90 AB, 100% purity, MS ESI C 30 H 47 O [M+H-2H2O] + Calculated value: 423, measured value: 423.

[0193] Example 19. Synthesis of Compound 15. [ka] Step 1. Synthesis of intermediate 15-1. To a flask containing THF (3 mL), -78 At −78° C., n-BuLi (1.44 mL, 3.60 mmol, 2.5 M) was added, followed by dropwise addition of a suspension of intermediate B-4 (500 mg, 1.03 mmol) in THF (5 mL) to give a light yellow suspension. After stirring at −78° C. for 30 min, a solution of intermediate 11-2 (352 mg, 3.09 mmol) in THF (2 mL) was added. The reaction was stirred at −78° C. for 10 min and at 15° C. for 16 h. The reaction was quenched with aqueous NH4Cl (50 mL) and extracted with DCM (3 × 50 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude intermediate 15-1 (500 mg) as a yellow solid, which was used directly in the next step. LCMS 1.5 min chromatography Rt = 0.973 min, 5-95 AB, purity 47%, MS ESI C 36 H 53 04S [M+H -H2O] + Calculated value 581, measured value 581.

[0194] Step 2. Synthesis of Compound 15. To a solution of intermediate 15-1 (500 mg, 0.834 mmol) in 20 mL of dry MeOH under N2, magnesium turnings (809 mg, 33.3 mmol) (activated with 0.5% aqueous HCl, water, dry ethanol, and MTBE) and NiCl2 (21.5 mg, 0.17 mmol) were added with stirring at 55 °C to initiate continuous hydrogen evolution. After adding two batches of magnesium turnings (809 mg), most of the starting material was consumed. The reaction mixture was quenched at 10 °C by adding 2 M HCl (40 mL) until all solids were completely dissolved. The resulting solution was extracted with DCM (3 × 50 mL), and the combined organic phase was washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (0% to 20% MeOH in DCM) to give the product, which was recrystallized from MeCN (20 mL) to give compound 15 (150 mg, 39%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 5.25-5.18 (m, 1H), 3.84-3.74 (m, 1H), 3.50-3.41 (m, 1H), 3.35-3.21 (m, 2H), 2.33-2.26 (m, 1H), 2.20-2.12 (m, 1H), 2.00-1.64 (m, 7H), 1.63-1.47 (m, 6H), 1.44-1.31 (m, 9H), 1.26-1.14 (m, 3H), 1.10-0.94 (m, 8H), 0.89-0.75 (m, 7H), 0.61 (s, 3H). LCMS 2.0 min chromatography Rt = 1.284 min, 30-90 AB, 100% purity, MS ESI C 30 H 47 O [M+H-2H2O] + Calculated value: 423, measured value: 423.

[0195] Example 20. Synthesis of Compound 16. [ka] To a solution of compound 1 (300 mg, 0.626 mmol) in MeOH (20 mL) was added Pd(OH) (100 mg, dry). The mixture was hydrogenated at 50 °C and 50 Psi for 48 h. The mixture was filtered, washed with DCM (100 mL), and the filtrate was concentrated. The residue was purified by silica gel chromatography (0-15% EtOAc in PE) to give compound 16 (114 mg, 38%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 2.20-2.00 (m, 2H), 1.99-1.75 (m, 4H), 1.70-1.60 (m, 5H), 1.59-1.42 (m, 8H), 1.41-1.23 (m, 6H), 1.22-1.16 (m, 6 H), 1.15-0.96 (m, 8H), 0.95-0.82 (m, 4H), 0.80 (s, 3H), 0.70-0.60 (m, 4H). LCMS 2.0 min chromatography Rt = 1.275 min, 30-90 AB, 100% purity, MS ESI C 30 H 47 F2[M+H-2H2O] + Calculated value: 445, measured value: 445.

[0196] Example 21. Synthesis of Compound 17. [ka] To a solution of compound 5-A (100 mg, 0.232 mmol) in MeOH (10 mL) was added dry Pd / C (100 mg) at 15 °C. The mixture was degassed and purged with H2 several times and stirred under 50 psi of H2 at 55 °C for 48 h. The reaction mixture was filtered to remove Pd / C, and the filtrate was concentrated. The resulting residue was purified by silica gel chromatography (0% to 30% EtOAc in PE / DCM (v / v = 1 / 1)) to give compound 17 (30 mg, 30%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 4.06-3.98 (m, 1H), 3.93-3.85 (m, 1H), 3.69 (d, J = 9.2 Hz, 1H), 3.54 (d, J = 9.2 Hz, 1H), 1.99-1.75 (m, 4H), 1.74-1.58 (m, 5H), 1.55-1.37 (m, 7H), 1.35-1.18 (m, 10H), 1.17-0.95 (m, 7H), 0.94-0.83 (m, 4H), 0.80 (s, 3H), 0.70-0.60 (m, 4H). LCMS 2.0 min chromatography Rt = 1.114 min, 30-90 AB, 100% purity, MS ESI C 28 H 45 O [M+H-2H2O] + Calculated value: 397, measured value: 397.

[0197] Example 22. Synthesis of Compound 18. [ka] To a solution of compound 6 (100 mg, 0.224 mmol) in MeOH (10 mL) was added dry Pd / C (100 mg) at 15 °C. The mixture was degassed and purged with H2 several times and stirred under 50 psi of H2 at 50 °C for 48 h. The reaction mixture was filtered to remove Pd / C, and the filtrate was concentrated. The resulting residue was purified by silica gel chromatography (0% to 30% EtOAc in PE / DCM (v / v = 1 / 1)) to give compound 18 (32 mg, 32.0%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 3.75-3.61 (m, 4H), 1.92-1.84 (m, 1H), 1.81-1.70 (m, 1H), 1.66-1.49 (m, 7H), 1.48-1.36 (m, 7H), 1.34-1.22 (m, 5H), 1.20-1.12 (m, 7H), 1.09-0.98 (m, 5H), 0.96-0.77 (m, 6H), 0.81 (s, 3H), 0.64-0.53 (m, 4H). LCMS 2.0 min chromatography Rt = 1.216 min, 30-90 AB, 100% purity, MS ESI C 29 H 47 O [M+H-2H2O] + Calculated value 411, measured value 411.

[0198] Example 23. Synthesis of Compound 19. [ka] To a solution of compound 11 (100 mg, 0.224 mmol) in MeOH (10 mL) was added dry Pd / C (100 mg) at 15 °C. The mixture was degassed and purged with H2 several times and stirred under 50 psi of H2 at 50 °C for 48 h. The reaction mixture was filtered to remove Pd / C, and the filtrate was concentrated. The resulting residue was purified by silica gel chromatography (0% to 30% EtOAc in PE / DCM (v / v = 1 / 1)) to give compound 19 (35.0 mg, 35%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 3.84-3.74 (m, 1H), 3.49-3.42 (m, 1H), 3.35-3.20 (m, 2H), 2.18-2.14 (m, 1H), 1.93-1.71 (m, 3H), 1.68-1.49 (m, 5H), 1.47-1.34 (m, 7H), 1.33-1.21 (m, 4H), 1.21-1.10 (m, 8H), 1.10-0.89 (m, 7H), 0.88-0.68 (m, 7H), 0.63-0.52 (m, 4H). LCMS 2 min chromatography Rt = 1.249 min, 30-90AB_E, 100% purity, MS ESI C 29 H 47 O [M+H -2H2O] + Calculated value 411, measured value 411.

[0199] Example 24. Synthesis of Compound 20. [ka] Step 1. Synthesis of Intermediate 20-1. To a solution of 2,6-di-tert-butyl-4-methylphenol (14.4 mg, 65.4 mmol) in toluene (100 mL), AlMe3 (16.3 mL, 32.7 mmol, 2 M in toluene) was added dropwise at 0 °C. The mixture was stirred at 25 °C for 1 hour to obtain a MAD solution. A solution of Intermediate C-7 (5 g, 10.9 mmol) in toluene (50 mL) was added dropwise to the MAD (116 ml, 0.28 M in toluene) reaction mixture at -65 °C. After stirring at -65 °C for 1 hour, MeMgBr (10.8 mL, 32.6 mmol, 3 M in ethyl ether) was added at -65 °C. The resulting solution was added dropwise at −65° C., and the resulting solution was stirred at −65° C. for 1 hour. The reaction was quenched with saturated aqueous NH4Cl (100 mL) at −65° C., and the mixture was warmed to 25° C. After stirring for 10 minutes, the resulting suspension was filtered through a Celite pad, and the pad was washed with EtOAc (100 mL). The combined organic layers were separated, washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give intermediate 20-1 (4.5 g crude) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 7.95-7.83 (m, 2H), 7.66-7.60 (m, 1H), 7.58-7.51 (m, 2H), 3.17-3.08 (m, 1H), 2.88-2.68 (m, 1H), 2.15-2.03 (m, 1H), 1.94-1.86 (m, 1H), 1.73-1.40 (m, 9H), 1.40-0.90 (m, 19H), 0.90-0.80 (m, 1H), 0.79 (s, 3H), 0.62 (s, 3H).

[0200] Step 2. Synthesis of Intermediate 20-2. To a solution of n-BuLi (504 μL, 2.5 M in hexane, 1.26 mmol) in THF (1 mL) was added dropwise a suspension of Intermediate 20-1 (200 mg, 0.423 mmol) in THF (3 mL) at −65° C. under N2. After stirring at −65° C. for 30 min, a solution of diisopropylamine (127 mg, 1.26 mmol) was added dropwise, followed by a solution of Intermediate 10-2 (176 mg, 1.26 mmol). The mixture was stirred at −65° C. for an additional 30 min, then gradually warmed to 25° C. and stirred for 16 h. The reaction was quenched with saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, and concentrated to give intermediate 20-2 (270 mg, crude), which was used directly in the next step.

[0201] Step 3. Synthesis of Compound 20. A solution of intermediate 20-2 (270 mg, 0.44 mmol) in MeOH (50 mL) was heated to 60 °C. One portion of NiCl (2.83 mg, 0.022 mmol) was added, followed by four portions of Mg (420 mg, 17.5 mmol). After stirring at 60 °C for 1 h, the reaction was quenched by adding HCl (10 mL, 2 M) until a clear solution was obtained, and the solution was extracted with DCM (2 × 20 mL). The combined organic phases were dried over Na SO , filtered, concentrated, and purified by silica gel chromatography (0-20% EtOAc in PE) to give compound 20 (100 mg, 48%). The product was dissolved in MeCN (25 mL), concentrated under reduced pressure at 70° C., triturated with water (5 mL), filtered, and concentrated to give compound 20 as an off-white solid (56 mg). 1 H NMR (400 MHz, CDCl3) δ 2.00-1.91 (m, 1H), 1.89-1.78 (m, 1H), 1.70-1.51 (m, 3H), 1.51-1.19 (m, 13H), 1.19-1.04 (m, 13H), 1.18-1.06 (m, 5H), 1.06-0.96 (m, 3H), 0.95-0.86 (m, 10H), 0.82-0.79(m, 3H), 0.70-0.60 (m, 4H). LCMS 2 min chromatography Rt = 1.442 min, 30-90AB_2MIN_E, purity 100%, MS ESI C 32 H 53 [M+H-2H2O] + Calculated value: 437, measured value: 437.

[0202] Example 25. Synthesis of Compound 21. [ka] Step 1. Synthesis of intermediate 21-1. Diisopropylamine (173 To a solution of Intermediate C-8 (300 mg, 0.616 mmol) in THF (3 mL) was added butyllithium (0.616 mL, 1.54 mmol, 2.5 M in n-hexane), and the mixture was stirred at −70° C. for 30 minutes. A solution of Intermediate C-8 (300 mg, 0.616 mmol) in THF (3 mL) was added, and the mixture was stirred at −70° C. for 30 minutes. Intermediate 1-2 (182 mg, 1.23 mmol) was added at −70° C., and the mixture was warmed to 25° C. and stirred at this temperature for 17 hours. The mixture was quenched with saturated NH4Cl (30 mL), extracted with EtOAc (3 × 10 mL), washed with brine (2 × 30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give Intermediate 21-1 (350 mg) as a yellow solid, which was used directly in the next step.

[0203] Step 2. Synthesis of Compound 21. A solution of intermediate 21-1 (350 mg, 0.551 mmol) in MeOH (15 mL) was heated to 55 °C, treated with one portion of Mg powder (547 mg, 22.8 mmol), and refluxed for 1 h. The reaction was quenched with HCl (50 mL, 1N), and the resulting clear solution was extracted with DCM (2 × 30 mL). The combined organic phases were dried over NaSO, filtered, concentrated, and purified by silica gel chromatography (0–10% EtOAc in PE) to give impure compound 21 (120 mg, 44% yield, containing the 22,23-olefin) as an off-white solid. This 120 mg impure sample was dissolved in THF (5 mL) and treated with Pd / C (100 mg, wet). The mixture was hydrogenated (15 Psi, 25° C.) for 2 h, filtered, concentrated, and purified by silica gel chromatography (0-15% EtOAc in PE) to give compound 21 (86 mg, 72%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 2.20-2.01 (m, 2H), 1.98-1.72 (m, 4H), 1.70-1.58 (m, 10H), 1.56-1.41 (m, 6H), 1.40-1.30 (m, 5H), 1.29-1.18 (m, 4H), 1.17-1.05 (m, 4H), 1.04-0.96 (m, 3H), 0.95-0.80 (m, 10H), 0.68-0.58 (m, 4H). LCMS 2.0 min chromatography Rt = 1.325 min, 30-90 AB, 100% purity, MS ESI C 31 H 49 F2[M+H-2H2O] + Calculated value: 459, measured value: 459.

[0204] Example 26. Synthesis of Compound 22. [ka] To a solution of compound 13 (160 mg, 0.391 mmol) in MeOH (15 mL) and THF (15 mL) was added Pd(OH) / C (dry, 350 mg) under N. The suspension was degassed and purged with H three times. The mixture was stirred under H (50 psi) at 50 °C for 48 h to give a black suspension. The reaction mixture was filtered through a pad of Celite, washed with THF (3 × 20 mL), and the filtrate was concentrated in vacuo to give compound 22 (12 mg, 8%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 2.00-1.91 (m, 1H), 1.91-1.73 (m, 1H), 1.69-1.56 (m, 5H), 1.54-1.44 (m, 9H), 1.44-1.41 (m, 1H), 1.41-1.32 (m, 4H), 1.32-1.15 (m, 9H), 1.15-1.04 (m, 5H), 1.04-0.95 (m, 3H), 0.95-0.91 (m, 5H), 0.91-0.89 (m, 2H), 0.89-0.85 (m, 6H), 0.85-0.79 (m, 3H), 0.69-0.60 (m, 4H) LCMS 2 min chromatography Rt = 1.515 min, 30-90AB, pure 100% MS ESI C 33 H 55 [M+H-2H2O] + Calculated value: 451, measured value: 451.

[0205] Example 27. Synthesis of Compound 23. [ka] To a solution of compound 14 (100 mg, 0.217 mmol) in MeOH (10 mL) was added dry Pd / C (100 mg) at 15° C. The mixture was degassed and purged with H several times and stirred under 50 psi of H at 55° C. for 48 h. The reaction mixture was filtered to remove Pd / C, the filtrate was concentrated, and the residue was purified by silica gel chromatography (0% to 30% EtOAc in PE / DCM (v / v=1 / 1)) to give compound 23 (36.0 mg, 36%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 3.82-3.69 (m, 4H), 1.99-1.91 (m, 1H), 1.87-1.75 (m, 1H), 1.73-1.57 (m, 7H), 1.55-1.42 (m, 7H), 1.40-1.17 (m, 10H), 1.16-0.95 (m, 8H), 0.94-0.84 (m, 7H), 0.82 (s, 3H), 0.70-0.55 (m, 4H). LCMS 2.0 min chromatography Rt = 1.208 min, 30-90 AB, 100% purity, MS ESI C 30 H 49 O [M+H-2H2O] + Calculated value: 425, measured value: 425.

[0206] Example 28. Synthesis of Compound 24. [ka] To a solution of compound 15 (100 mg, 0.217 mmol) in MeOH (10 mL) was added dry Pd / C (100 mg) at 15° C. The mixture was degassed and purged with H several times and stirred under 50 psi of H at 50° C. for 48 h. The reaction mixture was filtered to remove Pd / C, the filtrate was concentrated, and the residue was purified by silica gel chromatography (0% to 30% EtOAc in PE / DCM (v / v=1 / 1)) to give compound 24 (27 mg, 27%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 3.89-3.81 (m, 1H), 3.55-3.48 (m, 1H), 3.43-3.25 (m, 2H), 2.25-2.20 (m, 1H), 1.99-1.77 (m, 3H), 1.73-1.57 (m, 6H), 1.54-1.41 (m, 7H), 1.40-1.18 (m, 10H), 1.15-0.96 (m, 7H), 0.93-0.80 (m, 10H), 0.70-0.57 (m, 4H). LCMS 2.0 min chromatography Rt = 1.270 min, 30-90 AB, 100% purity, MS ESI C 30 H 49 O [M+H-2H2O] + Calculated value: 425, measured value: 425.

[0207] [Table 1-1] [Table 1-2] In Table 1, "A" indicates 10-100%, "B" indicates >100%-150% synergy, and "C" indicates >150% synergy.

[0208] The data in Table 1 demonstrate the ability of exemplary compounds to modulate the NMDA receptor as positive allosteric modulators (PAMs). Other embodiments

[0209] In the claims, articles (e.g., "a," "an," and "the") may mean one or more, unless indicated to the contrary or otherwise clear from the context. Any claim or description including "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, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one or all group members are present in, employed in, or otherwise relevant to a given product or process.

[0210] Furthermore, the present invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims are introduced into another claim. For example, any claim dependent on another claim can be modified to include one or more limitations found in any other claim dependent on the same base claim. Where elements are presented as a list, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element can be removed from the group. In general, when the invention or an aspect of the invention is referred to as comprising particular elements and / or features, it should be understood that certain embodiments of the invention or aspect of the invention consist of or consist essentially of such elements and / or features. For purposes of simplicity, those embodiments have not been explicitly recited in these exact terms herein. It should also be noted that the terms "comprising" and "containing" are intended to be open and allow for the inclusion of additional elements or steps. Where ranges are given, the endpoints are included. Furthermore, unless otherwise indicated or otherwise apparent from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges may, in various embodiments of the invention, assume any specific value or subrange within the range set forth to the tenth of the unit of the lower limit of that range, unless the context clearly dictates otherwise.

[0211] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any incorporated reference and this specification, the present specification shall control. Furthermore, any particular embodiment of the present invention that falls within the prior art may be expressly excluded from any one or more of the claims. Because such embodiments are deemed known to those of ordinary skill in the art, they may be excluded even if the exclusion is not expressly set forth herein. Any particular embodiment of the present invention may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0212] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the embodiments described herein is not intended to be limited to the above description, but is instead 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.

[0213] In one embodiment, for example, the following items are provided: (Item 1) Formula (IA): [ka] or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (IA): A is carbocyclyl or heterocyclyl; R 1 is C 1~6 is alkyl; R 5 is absent or hydrogen; [ka] represents a single or double bond, where one [ka] is a double bond, the other [ka] is a single bond, and R 5 does not exist, The compound or a pharmaceutically acceptable salt thereof. (Item 2) Formula (IB): [ka] or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (IB): R 1 is hydrogen or C 1~6 is alkyl; R 5 is absent or hydrogen; Z is -C(R A )2-, -NR B -, -O-, or -S-; X is halogen, C 1~6 Alkyl, or -OR C and; R A is hydrogen, halogen, or C 1~6 is alkyl; R B is hydrogen, C 1~6 Alkyl, -C(O)R C , -C(O)OR C , -C(O)N(R D )2, or -S(O)2R C and; R C is hydrogen or C 1~6 is alkyl; Each R D are independently hydrogen, C 1~6 is alkyl, aryl, or heteroaryl; m is an integer selected from 1, 2, and 3; n is an integer selected from 1, 2, and 3; p is an integer selected from 0, 1, 2, 3, 4, and 5; and [ka] represents a single or double bond, where one [ka] is a double bond, the other [ka] is a single bond, and R 5 does not exist, The compound or a pharmaceutically acceptable salt thereof. (Item 3) The compound has formula (II-A), formula (II-B), or formula (II-C): [ka] Item 3. The compound according to item 2, wherein the compound is (Item 4) 3. The compound according to item 2, wherein p is an integer selected from 0, 1, or 2. (Item 5) 3. The compound according to item 2, wherein p is 0. (Item 6) 3. The compound according to item 2, wherein p is 1. (Item 7) 3. The compound according to item 2, wherein p is 1 and X is a halogen. (Item 8) The compound has formula (II-D), formula (II-E), or formula (II-F): [ka] Item 4. The compound according to item 3, wherein the compound is (Item 9) R 1 is C 1~6 The compound according to item 2, wherein the aryl group is alkyl. (Item 10) R 1is methyl or ethyl. (Item 11) R 1 is -CH3 or -CH2CH3. (Item 12) The compound has formula (II-G) or formula (II-H): [ka] [ka] Item 3. The compound according to item 2, wherein the compound is (Item 13) The compound has formula (II-I) or formula (II-J): [ka] Item 3. The compound according to item 2, wherein the compound is (Item 14) Z is -C(R A )2-, -O-, or -NR B (Item 15) The compound according to Item 2, wherein R A The compound according to item 2, wherein is a halogen. (Item 16) Item 3. The compound according to item 2, wherein Z is —CH2—, —CF2—, or —C(CH3)2—. (Item 17) Z is -O- or -NR B Item 3. The compound according to item 2, wherein (Item 18) 3. The compound according to item 2, wherein Z is -NH-, -NMe-, or -NAc-. (Item 19) The compound according to item 2, wherein Z is -CH2-. (Item 20) The compound according to item 2, wherein Z is —C(CH 3 ) 2 —. (Item 21) The compound according to item 2, wherein Z is -CF2-. (Item 22) The compound according to item 2, wherein m is 1, n is 2, and Z is -O-. (Item 23) The compound according to item 2, wherein m is 2 and n is 2. (Item 24) 3. The compound according to item 2, wherein m is 3 and n is 1. (Item 25) The compound according to item 2, wherein m is 3, n is 1, and Z is -O-. (Item 26) m is 2, n is 2, and Z is -O- or -NR B Item 3. The compound according to item 2, wherein (Item 27) [ka] [ka] [ka] A compound selected from: (Item 28) [ka] [ka] [ka] A pharmaceutically acceptable salt of a compound selected from: (Item 29) A pharmaceutical composition comprising a compound according to any one of items 1 to 28 and a pharmaceutically acceptable carrier. (Item 30) A method for inducing sedation or anesthesia, comprising administering to a subject an effective amount of a compound according to any one of items 1 to 28 or a pharmaceutical composition thereof. (Item 31) A method for treating or preventing a disorder described herein, comprising administering to a subject in need of said treatment or prevention an effective amount of a compound described in any one of items 1 to 28 or a pharmaceutical composition thereof. (Item 32) 32. The method according to item 31, wherein the disorder is a gastrointestinal (GI) disorder, a structural disorder affecting the GI, a disorder of the anus, a colon polyp, cancer, colitis. (Item 33) 32. The method of claim 31, wherein the disorder is inflammatory bowel disease. (Item 34) Item 35. The method according to Item 31, wherein the disorder is cancer, diabetes, or a sterol synthesis disorder. 32. The method of claim 31, wherein the disorder is a metabolic disorder. (Item 36) A method for treating or preventing a CNS-related condition, comprising administering to a subject in need of said treatment or prevention an effective amount of a compound according to any one of items 1 to 28 or a pharmaceutical composition thereof. (Item 37) 37. The method of item 36, wherein the CNS-related condition is an adjustment disorder, an anxiety disorder, a cognitive disorder, a dissociative disorder, an eating disorder, a mood disorder, a bipolar disorder, a dysthymic disorder, suicidality, schizophrenia or other psychotic disorder, a sleep disorder, a substance-related disorder, a personality disorder, an autism spectrum disorder, a neurodevelopmental disorder, multiple sclerosis, a sterol synthesis disorder, pain, a brain injury secondary to a medical condition, a seizure disorder, a stroke, a traumatic brain injury, a movement disorder, a visual disorder, a hearing disorder, and tinnitus. (Item 38) 37. The method of claim 36, wherein the disorder is a sterol synthesis disorder. (Item 39) 29. A method for treating or preventing an autism disorder associated with Smith-Lemli-Opitz syndrome (SLOS), desmosterolosis, sitosterolemia, cerebrotendinous xanthomatosis (CTX), mevalonate kinase deficiency syndrome (MKD), SC4MOL gene mutation (SMO deficiency), Niemann-Pick disease, or phenylketonuria, comprising administering to a subject in need of said treatment or prevention an effective amount of the compound according to any one of items 1 to 28 or a pharmaceutical composition thereof.

Claims

[Claim 1] The need for novel oxysterols.

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