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) in the figure, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. In the formula, A is carbocyclyl or heterocyclyl; R1 is C1-6 alkyl (e.g., -CH3 or -CH2CH3); and R5 is absent or hydrogen. Also provided are pharmaceutical compositions containing the compounds, and methods of their use and treatment.SELECTED DRAWING: None

Description

Technical Field

[0001] Claims of Priority This application claims priority to U.S. Application No. 62 / 317,002, filed on April 1, 2016, the entire disclosure of which is incorporated herein by reference.

Background Art

[0002] Background of the Invention The NMDA receptor is a heteromeric complex that includes NR1, NR2, and / or NR3 subunits and has different recognition sites for exogenous and endogenous ligands. These recognition sites include a binding site for glycine as well as glutamate agonists and modulators. The NMDA receptor is expressed in peripheral tissues and the CNS, where it is involved in excitatory synaptic transmission. Activation of these receptors can, depending on the situation, contribute to synaptic plasticity or, in other cases, excitotoxicity. These receptors are ligand-gated ion channels that accept Ca2+ after the binding of glutamate and glycine and are fundamental for excitatory neurotransmission and normal CNS function. Positive modulators of these receptors can be useful as cognitive enhancers and as therapeutic agents having potential clinical utility in the treatment of mental disorders in which glutamatergic transmission is reduced or deficient (see, for example, Horak et al., J. of Neuroscience, 2004, 24(46), 10318-10325). In contrast, negative modulators of these receptors can be useful as therapeutic agents having potential clinical utility in the treatment of psychiatric disorders (e.g., treatment-resistant depression) in which glutamatergic transmission is pathologically increased. Oxysterols are cholesterol analogs that are modulators of NMDA receptor function. There is a need for novel oxysterols that regulate the NMDA receptor for the prevention and treatment of conditions associated with the expression and function of NMDA. The compounds, compositions, and methods described herein are directed to this end.

Prior Art Documents

Non-Patent Documents

[0003]

Non-Patent Document 1

Summary of the Invention

Means for Solving the Problems

[0004] Gist 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). Further provided are pharmaceutical compositions containing the compounds of the invention, as well as methods of using and treating these. In one aspect, a compound of formula (I-A):

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[0005] In one aspect, there is provided herein a pharmaceutical composition comprising a compound as described herein (e.g., of formula (I-A), (I-B), (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 and a pharmaceutically acceptable carrier thereof. In another aspect, a method of inducing sedation or anesthesia is provided herein, the method comprising administering to a subject an effective amount of a compound as described herein (e.g., of formula (I-A), (I-B), (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, a method for treating or preventing a disorder described herein is provided herein, the method comprising administering to a subject in need thereof an effective amount of a compound as described herein (e.g., of formula (I-A), (I-B), (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, for example, constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) (e.g., ulcerative colitis, Crohn's disease), structural disorders affecting the GI, anorectal disorders (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas), colorectal 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, 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., of formula (I-A), (I-B), (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, is provided herein.

[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, cyclothymic disorder, and suicidal tendencies), schizophrenia or other psychotic disorder (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 involving mutations in Shank family 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 secondary brain disorder to a medical condition (including hepatic encephalopathy and anti-NMDA receptor encephalitis), a seizure disorder (including status epilepticus and single-gene forms of epilepsy, e.g., Dravet's disease), a stroke, a traumatic brain injury, a movement disorder (including Huntington's disease and Parkinson's disease), a visual disorder, an auditory disorder, and tinnitus.

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

[0014] In one aspect, methods 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 are provided herein, the methods comprising administering to a subject in need of such treatment or prevention an effective amount of a compound as described herein (e.g., of formula (I-A), (I-B), (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] 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., of formula (I-A), (I-B), (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, is provided herein. 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, cyclothymic disorder, suicidal tendency, 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 comprising mutations to Shank family 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 (including status epilepticus and single-gene forms of epilepsy, e.g., Dravet syndrome), a stroke, a traumatic brain injury, a movement disorder (including Huntington's disease and Parkinson's disease), a visual disorder, an auditory disorder, and tinnitus. Definitions Chemical Definitions

[0017] The definitions of specific functional groups and chemical terms are described in detail below. Chemical elements are specified according to the Periodic Table of the Elements (CAS version, Handbook of Chemistry and Physics, 75th Edition, inside front cover), and specific functional groups are generally defined as described therein. Further, the general rules of organic chemistry, as well as 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] Compounds described herein may contain one or more asymmetric centers and thus may exist as various isomers, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers or geometric isomers, or in the form of mixtures 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 performance liquid chromatography (HPLC), supercritical fluid chromatography (SFC), and the formation and crystallization of chiral salts); or the preferred isomers can be prepared by asymmetric synthesis. For example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wil See also: en et al., Tetrahedron 33:2725(1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (edited by E.L. Eliel, Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention further includes the compounds described herein as individual isomers substantially free of other isomers and / or as mixtures of various isomers.

[0019] In one embodiment, the stereoisomers described herein are enriched in the stereoisomeric forms depicted for the compound. For example, the stereoisomers can have an enantiomeric excess 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 recited, it is intended to include each value and sub-range within that range. For example, "C 1~6 alkyl" is intended to include 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 alkyl.

[0021] The following terms are intended to have the meanings set forth below with respect thereto 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, any of the moieties defined below may be substituted with various substituents, and each definition is also intended to encompass the substituted moieties within their scope as described below. Unless otherwise stated, the term "substituted" is defined as described below. It should be further understood that the terms "group" and "radical" may be considered interchangeable as used herein. The articles "a" and "an" may be used herein to refer to the grammatical object of the article being one or more (i.e., at least one). By way of example, "an analogue" means one analogue or more than one analogue.

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

[0023] "Alkyl" refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms ("C 1~20 alkyl"). In some embodiments, the alkyl group has from 1 to 12 carbon atoms ("C 1~12 alkyl"). In some embodiments, the alkyl group has from 1 to 10 carbon atoms ("C 1~10 alkyl"). In some embodiments, the alkyl group has from 1 to 9 carbon atoms ("C 1~9 alkyl"). In some embodiments, the alkyl group has from 1 to 8 carbon atoms ("C 1~8 alkyl"). In some embodiments, the alkyl group has from 1 to 7 carbon atoms ("C1~7 "alkyl"). In some embodiments, the alkyl group has from 1 to 6 carbon atoms (also referred to herein as "lower alkyl" "C 1~6 alkyl"). In some embodiments, the alkyl group has from 1 to 5 carbon atoms ("C 1~5 alkyl"). In some embodiments, the alkyl group has from 1 to 4 carbon atoms ("C 1~4 alkyl"). In some embodiments the alkyl group has from 1 to 3 carbon atoms ("C 1~3 alkyl"). In some embodiments, the alkyl group has from 1 to 2 carbon atoms ("C 1~2 alkyl"). In some embodiments, the alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, the alkyl group has from 2 to 6 carbon atoms ("C 2~6 alkyl"). C 1~6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanil (C5), tertiary amyl (C5) and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc. 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, substituted with from 1 to 5 substituents, from 1 to 3 substituents or 1 substituent ("substituted alkyl"). In certain embodiments, the alkyl group is unsubstituted C 1~10 alkyl (e.g., -CH3). In certain embodiments, the alkyl group is substituted C 1~10It is alkyl. Common abbreviations for alkyl include Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2).

[0024] "Alkylene" refers to an alkyl group from which two hydrogens have been removed to give a divalent radical, which may or may not be substituted. Examples of unsubstituted alkylene groups include methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), and hexylene (-CH2CH2CH2CH2CH2CH2-), but are not limited thereto. 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)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), but are not limited thereto. When a range or number of carbons is provided for a particular alkylene group, it is understood that this range or number refers to the range or number of carbons in the straight-chain divalent carbon chain. The alkylene group may or may not be substituted with one or more substituents as described herein.

[0025] "Alkenyl" refers to a radical of a straight-chain or branched-chain hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) (the "C" 2~20refers to "alkenyl". In certain embodiments, alkenyl contains no triple bonds at all. In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C 2~10 alkenyl"). In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C 2~9 alkenyl"). In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C 2~8 alkenyl"). In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C 2~7 alkenyl"). In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C 2~6 alkenyl"). In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C 2~5 alkenyl"). In some embodiments , the alkenyl group has 2 to 4 carbon atoms ("C 2~4 alkenyl"). In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2~3 alkenyl"). In some embodiments, the alkenyl group has 2 carbon atoms ("C2 alkenyl"). One or more carbon-carbon double bonds can be present internally (e.g., 2-butenyl) or terminally (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. C 2~6 Examples of alkenyl groups include the above-mentioned C 2~4Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrieneyl (C8), etc. 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, the alkenyl group is unsubstituted C 2~10 alkenyl. In certain embodiments, the alkenyl group is substituted C 2~10 alkenyl.

[0026] "Alkynyl" refers to a radical of a straight-chain or branched-chain hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) ( "C 2~20 alkynyl"). In certain embodiments, alkynyl contains no carbon-carbon double bonds at all. In some embodiments, the alkynyl group has 2 to 10 carbon atoms ( "C 2~10 alkynyl"). In some embodiments, the alkynyl group has 2 to 9 carbon atoms ( "C 2~9 alkynyl"). In some embodiments, the alkynyl group has 2 to 8 carbon atoms ( "C 2~8 alkynyl"). In some embodiments, the alkynyl group has 2 to 7 carbon atoms ( "C 2~7 alkynyl"). In some embodiments, the alkynyl group has 2 to 6 carbon atoms ( "C 2~6 alkynyl"). In some embodiments, the alkynyl group has 2 to 5 carbon atoms ( "C 2~5 alkynyl"). In some embodiments, the alkynyl group has 2 to 4 carbon atoms ( "C 2~4"alkynyl"). In some embodiments, the alkynyl group has from 2 to 3 carbon atoms ("C 2~3 alkynyl"). In some embodiments, the alkynyl group has 2 carbon atoms ("C2 alkynyl"). 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. C 2~6 Examples of alkenyl groups include the C 2~4 alkynyl groups described above, as well as 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, the alkynyl group is unsubstituted C 2~10 alkynyl. In certain embodiments, the alkynyl group is substituted C 2~10 alkynyl.

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

[0028] "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) with 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system, a radical of which ( 6~14 "C 10 aryl"). In some embodiments, the aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has 10 ring carbon atoms ( 14 "C is substituted with one or more substituents (a "substituted aryl"). In certain embodiments, the aryl group is unsubstituted C 6~14 aryl. In certain embodiments, the aryl group is substituted C 6~14 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] Examples of representative substituted aryls include the following

Chemical formula

[0031] "Condensed aryl" refers to aryl in which two of its ring carbons are common with a second aryl ring or heteroaryl ring, or with a carbocyclic ring or heterocyclic ring.

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

[0033] "Heteroaryl" refers to a radical of a 5-10 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 one to four ring heteroatoms are provided in an aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In a heteroaryl group containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom when the valence allows. The heteroaryl bicyclic ring system can 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 carbocyclic groups or heterocyclic groups, where the point of attachment is on the heteroaryl ring, and in such cases, the number of ring members continues to refer to the number of ring members within the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups, where the point of attachment is on the aryl ring or on the heteroaryl ring, and in such cases, the number of ring members refers to the number of ring members within the fused (aryl / heteroaryl) ring system. A bicyclic heteroaryl group in which one ring does not contain a heteroatom (e.g., indolyl) Indolyl, quinolinyl, carbazolyl, etc.), and the point of attachment may be on any ring, i.e., on a ring having a heteroatom (e.g., 2-indolyl) or a ring not containing a heteroatom (e.g., 5-indolyl).

[0034] In some embodiments, the heteroaryl group is a 5- to 10-membered aromatic ring system in which ring carbon atoms and one to four ring heteroatoms are provided to the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 10-membered heteroaryl”). In some embodiments, the heteroaryl group is a 5- to 8-membered aromatic ring system in which ring carbon atoms and one to four ring heteroatoms are provided to the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heteroaryl”). In some embodiments, the heteroaryl group is a 5- to 6-membered aromatic ring system in which ring carbon atoms and one to four ring heteroatoms are provided to the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heteroaryl”). In some embodiments, the 5- to 6-membered heteroaryl has one to three ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has one to two ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each occurrence of the heteroaryl group is independently optionally substituted, i.e., unsubstituted (“unsubstituted heteroaryl”) or substituted with one or more substituents (“substituted heteroaryl”). In certain embodiments, the heteroaryl group is unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is 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-fused 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-fused bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0036] Examples of representative heteroaryls include the following:

Chemical Structure

[0037] "Heteroalkyl" 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" refers to a radical of a non-aromatic ring system having 3 to 10 ring carbon atoms ("C 3~10 carbocyclyl") and 0 heteroatoms. In some embodiments, the carbocyclyl group has 3 to 8 ring carbon atoms ("C 3~8 carbocyclyl"). In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 carbocyclyl"). In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 carbocyclyl"). In some embodiments, the carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10 carbocyclyl"). Exemplary C 3~6 carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. Exemplary C 3~8 carbocyclyl groups include the above-mentioned C 3~6Carbocyclic groups, and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), etc. are included but not limited thereto. Exemplary C 3~10 As the carbocyclic group, the above-mentioned C 3~8 Carbocyclic groups, and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), etc. are included but not limited thereto. When the above examples are illustrated, in certain embodiments, the carbocyclic group is monocyclic ("monocyclic carbocyclic"), or includes a fused ring system, a bridged ring system or a spiro ring system (e.g., a bicyclic system ("bicyclic carbocyclic")), and can be saturated or partially unsaturated. "Carbocyclic" also includes a ring system in which one or more carbocyclic rings as defined above are fused with one or more aryl groups or heteroaryl groups, where the bonding point is on the carbocyclic ring, and in such cases, the number of carbons continues to refer to the number of carbons in the carbocyclic ring system. Unless otherwise specified, each occurrence of the carbocyclic group is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclic") or substituted with one or more substituents ("substituted carbocyclic"). In certain embodiments, the carbocyclic group is unsubstituted C 3~10 carbocyclic. In certain embodiments, the carbocyclic group is substituted C 3~10 carbocyclic.

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

[0040] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and one to four ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In a heterocyclyl group containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom when the valence allows. The heterocyclyl group can be a monocyclic ring system ("monocyclic heterocyclyl") or a fused ring system, a bridged ring system, or a spiro ring system (e.g., a bicyclic system ("bicyclic heterocyclyl")), and can be saturated or partially unsaturated. The bicyclic heterocyclic ring system can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes a ring system in which a heterocyclyl ring as defined above is fused with one or more carbocyclic groups, where the point of attachment is on the carbocyclic or heterocyclyl ring, or on a ring system in which a heterocyclyl ring as defined above is fused with one or more aryl groups or heteroaryl groups, where the point of attachment is on the heterocyclyl ring, and in such cases, the number of ring members continues to refer to the number of ring members within 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, the 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 (“5- to 10-membered heterocyclyl”). In some embodiments, the 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 (“5- to 8-membered heterocyclyl”). In some embodiments, the heterocyclyl group is a 5- to 6-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 (“5- to 6-membered heterocyclyl”). In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0042] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiirenyl. 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 pyrrol-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 fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocyclic rings) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0043] The term "nitrogen-containing heterocyclyl" group means a 4- to 7-membered non-aromatic cyclic group containing at least one nitrogen atom, for example, 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-alkylpiperazine (e.g., N-methylpiperazine). Specific examples include azetidine, piperidone, and piperazone.

[0044] When used to describe a compound or a group present on a compound, "hetero" means that one or more carbon atoms in the compound or group are replaced by nitrogen, oxygen, or sulfur heteroatoms. 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" refers to a -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" is R 20is an acyl group which is a group other than hydrogen. Representative acyl groups include formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), --C(O)-C1-C8 alkyl, -C(O)-(CH2) t (C6-C 10 aryl), -C(O)-(CH2) t (5- to 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), but are not limited thereto. In certain embodiments, R 21 is C1-C8 alkyl substituted with halo or hydroxy; or C3-C 10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 aryl, arylalkyl, 5- to 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" refers to an -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. Specific alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1,2-dimethylbutoxy. Specific alkoxy groups are lower alkoxy, i.e., having 1 to 6 carbon atoms. Further specific alkoxy groups have 1 to 4 carbon atoms.

[0047] In certain embodiments, R 29 is one or more substituents selected from the group consisting of amino, substituted amino, C6-C 10 aryl, aryloxy, carboxyl, cyano, C3-C 10 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, in particular 1 to 3 substituents, in particular a group having 1 substituent. Exemplary "substituted alkoxy" groups include -O-(CH2) t (C6-C 10 aryl), -O-(CH2) t (5- to 10-membered heteroaryl), -O-(CH2) t (C3-C 10 cycloalkyl) and -O-(CH2) t (4- to 10-membered heterocyclyl), but are not limited thereto, where t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl or heterocyclyl group present may itself be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy. Particularly exemplary "substituted alkoxy" groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH and -OCH2CH2NMe2.

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

[0049] "Substituted amino" refers to an amino 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 Lucinyl, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group or an amino protecting group, wherein R 38 at least one of which is not hydrogen. In certain embodiments, each R 38 is independently hydrogen, C1-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C6-C 10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic 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 heterocyclic), where t is an integer from 0 to 8, each of which is 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 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- to 10-membered heterocyclyl) is exemplified, but not limited thereto, where t is an integer from 0 to 4, for example, 1 or 2, and each R 39 independently represents 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. To avoid misunderstanding, the term "substituted amino" includes alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino and substituted dialkylamino groups as defined below. Substituted amino includes both mono-substituted amino groups and di-substituted amino groups.

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

[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, the 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.

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

[0059] As defined herein, alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl groups are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclic, "substituted" or "unsubstituted" heterocyclic, "substituted" or "unsubstituted" aryl or "substituted" or "unsubstituted" heteroaryl groups). Generally, the term "substituted" means that at least one hydrogen present on a given group (e.g., a carbon or nitrogen atom), whether or not preceded by the term "optionally", is replaced by an acceptable substituent, e.g., a substituent that, when substituted, results in a stable compound, e.g., a compound that does not undergo spontaneous transformation (e.g., by rearrangement, cyclization, elimination or other reaction). Unless otherwise indicated, a "substituted" group has substituents at one or more of the substitutable positions of that group, and when two or more positions in any given structure are substituted, the substituents are the same or different at each position. The term "substituted" is intended to include substitution by all acceptable substituents of organic compounds, by any of the substituents described herein that form stable compounds. The present invention contemplates any and all such combinations for the purpose of obtaining stable compounds. For the purposes of the present invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents as described herein that satisfy the valence of the heteroatom and, as a result, form stable moieties.

[0060] Exemplary carbon atom substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb ), -N(R bb ), -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 carbocyclic, 3- to 14-membered heterocyclic, C 6~14 aryl and 5 - to 14-membered heteroaryl, including, but not limited to, where each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups; or

[0061] alternatively, two geminal hydrogens on a carbon atom are replaced with =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 groups;

[0062] R aaEach occurrence is independently C 1~10 alkyl, C 1~10 perhaloalkyl, C 2~10 alkenyl, C 2~10 alkynyl, C 3~10 carbocyclic, 3- to 14-membered heterocyclic, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R aa groups are linked to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups;

[0063] R bb Each occurrence 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 carbocyclic, 3- to 14-membered heterocyclic, C 6~14Selected from aryl and 5- to 14-membered heteroaryl, or two R bb 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 is independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups;

[0064] R cc each occurrence of which 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 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 is independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups;

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

[0066] R ee Each occurrence of which is independently selected from C 1~6 alkyl, C 1~6 perhaloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 carbocyclic, C 6~10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, where each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;

[0067] R ff Each occurrence of which is independently hydrogen, C 1~6 alkyl, C 1~6 perhaloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 carbocyclic, 3- to 10-membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, or two R ff groups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;

[0068] R gg Each occurrence of which is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C 1~6 alkyl)3 + X - , -NH(C 1~6 alkyl)2 + X- ,-NH2(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 Carbocyclic, C 6~10 Aryl, 3 to 10-membered heterocyclic, 5 to 10-membered heteroaryl; or two geminal R gg substituents may be linked to form =O or =S; where X - is a counterion.

[0069] "Counterion" or "anionic counterion" is a negatively charged group that associates with a cationic quaternary amino group to maintain electrical neutrality. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , OH - , H2PO4 - , HSO4 - , SO4 -2Sulfonate 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.) are included.

[0070] The nitrogen atom can be substituted or unsubstituted when its valence allows, and can 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 carbocyclic, 3- to 14-membered heterocyclic, C 6~14Aryl and 5- to 14-membered heteroaryl are included, but not limited thereto, or two Rs bonded to a nitrogen atom cc 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 is independently substituted with 0, 1, 2, 3, 4 or 5 Rs dd groups, and R aa , R bb , R cc and R dd are as defined above.

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

[0072] The term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals within the scope of sound medical judgment, without undue toxicity, irritation, allergic response, etc., 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, sho Examples include unioate, borneol sulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, 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 suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1~4 alkyl)4 salts. Representative alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide ions, hydroxide ions, carbonate ions, sulfate ions, phosphate ions, nitrate ions, lower alkyl sulfonate ions, and aryl sulfonate ions when appropriate.

[0073] The "subjects" for which administration is contemplated include humans (i.e., males or females 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, such as mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats and / or dogs), but are not limited thereto. 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] The terms disease, disorder, and condition are used interchangeably herein.

[0075] As used herein, unless otherwise specified, the terms "treat", "treating" and "treatment" of a compound are taken to mean an action (a "therapeutic treatment") that is carried out while a subject is suffering from a particular disease, disorder or condition and that reduces the severity of, or delays or slows the progression of, the disease, disorder or condition, and also an action (a "preventive treatment") that is carried out before a subject begins to suffer from a particular disease, disorder or condition.

[0076] Generally, an "effective amount" of a compound means an amount sufficient to elicit the desired biological response. As will be understood by those skilled in the art, the effective amount of the compounds of the present invention may vary depending on factors such as the desired biological goal, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health and condition of the subject. The effective amount includes both therapeutic treatment and preventive 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" may include an amount that improves the overall treatment, an amount that reduces or avoids the symptoms or causes of the 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" may include an amount that improves the overall prophylaxis, or an amount that enhances the prophylactic efficacy of another prophylactic agent. Abbreviations

[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: Isopropylmagnesium chloride; MAD: Methylaluminium bis(2,6-di-t-butyl-4-methylphenoxide); m-CPBA: Meta-chloroperbenzoic acid; Me3SI: Trimethylsulfonium 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(dichloro)dimethylsilane; TFA: Trifluoroacetic acid; THF: Tetrahydrofuran; Ts: p-Toluenesulfonyl; (i-PrO)4Ti: Titanium tetraisopropoxide.

Mode for Carrying Out the Invention

[0080] Detailed Description of Specific Embodiments of the Invention As generally described above, the present invention provides novel oxysterols useful for preventing and / or treating a wide range of disorders (including but not limited to NMDA-mediated disorders). Compound In one aspect, formula (I-A):

Chemical Formula

Chem.

Chem.

Chem.

Chem.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

[0081] In another aspect, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound as described herein (e.g., of formula (I-A), (I-B), (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 a medicament, the compounds provided herein are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared by methods well known in the pharmaceutical art and can contain at least one active compound.

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

[0084] The present invention also relates to a compound as described herein (e.g., of formula (I-A), (I-B), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J)), or a pharmaceutical composition thereof, for use as a medicament or medicine. or (II-J)), or a pharmaceutical composition thereof.

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

[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 route of delivery, the compounds provided herein are preferably formulated either as an injectable or oral composition, or as an ointment, as a lotion, or as a patch (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, the compositions are provided in unit dosage forms that facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unit doses for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, together with suitable pharmaceutical excipients. Typical unit dosage forms include pre-measured and pre-filled ampoules or syringes of liquid compositions, or in the case of solid compositions, pills, tablets, capsules, etc. 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), and the remainder are various vehicles or carriers and processing aids useful in forming the desired dosage form.

[0088] Liquid forms suitable for oral administration can include suitable aqueous or non-aqueous vehicles containing buffering agents, suspending agents and dispensing agents, coloring agents, flavoring agents, etc. Solid forms can include, for example, any of the following components or compounds of similar nature: binders (e.g., microcrystalline cellulose, tragacanth gum or gelatin); excipients (e.g., starch or lactose), disintegrants (e.g., alginic acid, Primogel or corn starch); lubricants (e.g., magnesium stearate); glidants (e.g., colloidal silicon dioxide); sweetening agents (e.g., sucrose or saccharin); or flavoring agents (e.g., peppermint, methyl salicylate or orange flavor).

[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 compounds in such compositions are typically trace components, often in an amount of about 0.05 to 10% by weight, and the remainder is an injectable carrier or the like.

[0090] Transdermal compositions are typically formulated as topical ointments or creams that contain the active ingredient(s) in an amount generally in the range of about 0.01 to about 20% by weight, preferably in the range of about 0.1 to about 20% by weight, preferably in the range of about 0.1 to about 10% by weight, and more preferably in the range of about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredient is typically admixed with a paraffin ointment base or a water-miscible ointment base. Alternatively, the active ingredient can be formulated as a cream, for example, containing an oil-in-water cream base. Such transdermal formulations are well known in the art and generally contain 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 transdermal devices. Thus, transdermal administration can be achieved using a reservoir type or a porous membrane type or a solid matrix type patch.

[0092] The components described above for orally administrable, injectable, or topically administrable compositions are merely representative. Other materials and processing techniques, etc., are shown in Remington’s Pharmaceutical Sciences, 17th Edition, 1985, Mack Publishing Company, Easton, Pennsylvania, Part 8 (incorporated herein by reference).

[0093] ​The components described above for an orally administrable, injectable, or locally administrable composition are merely representative. Other materials as well as processing techniques, etc. are shown in Remington’s The Science and Practice of Pharmacy, 21st Edition, 2005, Publisher: Lippincott Williams & Wilkins, Part 8 (incorporated herein by reference).

[0094] The compounds of the present invention can also be administered in a sustained release form or from a sustained release drug delivery system. A description of representative sustained release materials can be found in Remington’s Pharmaceutical Sciences.

[0095] The present invention also relates to a pharmaceutically acceptable formulation of a compound of formula (I). In one embodiment, the formulation contains water. In another embodiment, the formulation contains a cyclodextrin derivative. The most common cyclodextrins are α-, β- and γ-cyclodextrins, each consisting of 6, 7 and 8 α-1,4-linked glucose units, optionally containing one or more substituents on the linked sugar moieties (including, but not limited to, methylation, hydroxyalkylation, acylation and sulfoalkyl ether substitution). In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, also known as Captisol®. See, for example, U.S. Patent No. 5,376,645. In certain embodiments, the above formulation contains heptapropyl-β-cyclodextrin. In a further particular embodiment, the above formulation contains heptapropyl-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 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, etc.).

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

[0098] Exemplary formulation 1 - Tablet: A compound of formula (I-A), or a pharmaceutically acceptable salt thereof, can be mixed as a dry powder with a dry gelatin binder in an approximate weight ratio of 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into tablets of 240 - 270 mg (80 - 90 mg of the active compound per tablet) using a tableting machine.

[0099] Exemplary formulation 2 - Capsule: A compound of formula (I-A), or a pharmaceutically acceptable salt thereof, can be mixed as a dry powder with a starch diluent in an approximate weight ratio of 1:1. The mixture is filled into 250 mg capsules (125 mg of the active compound per capsule).

[0100] Exemplary formulation 3 - Liquid: A compound of formula (I-A), or a pharmaceutically acceptable salt thereof (125 mg), can be mixed with sucrose (1.75 g) and xanthan gum (4 mg), and the resulting mixture is mixed and passed through a No. 10 mesh U.S. sieve, then mixed with a pre-prepared aqueous solution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50 mg). Sodium benzoate (10 mg), flavor, and coloring agent are diluted with water and added with stirring. Then, sufficient water can be added to make the total volume 5 mL.

[0101] Exemplary formulation 4 - tablets: A compound of formula (I-A), or a pharmaceutically acceptable salt thereof, can be mixed as a dry powder with a dry gelatin binder in an approximate weight ratio of 1:2. A trace amount of magnesium stearate is added as a lubricant. The mixture is formed into tablets of 450 - 900 mg (150 - 300 mg of the active compound) using a tableting machine.

[0102] Exemplary formulation 5 - injection: A compound of formula (I-A), or a pharmaceutically acceptable salt thereof, can be dissolved or suspended in a sterile buffered saline injectable aqueous medium at a concentration of approximately 5 mg / mL.

[0103] Exemplary formulation 6 - tablets: A compound of formula (I-A), or a pharmaceutically acceptable salt thereof, can be mixed as a dry powder with a dry gelatin binder in an approximate weight ratio of 1:2. A trace amount of magnesium stearate is added as a lubricant. The mixture is formed into tablets of 90 - 150 mg (30 - 50 mg of the active compound per tablet) using a tableting machine.

[0104] Exemplary formulation 7 - tablets: A compound of formula (I-A), or a pharmaceutically acceptable salt thereof, can be mixed as a dry powder with a dry gelatin binder in an approximate weight ratio of 1:2. A trace amount of magnesium stearate is added as a lubricant. The mixture is formed into tablets of 30 - 90 mg (10 - 30 mg of the active compound per tablet) using a tableting machine.

[0105] Exemplary formulation 8 - tablets: A compound of formula (I-A), or a pharmaceutically acceptable salt thereof, can be mixed as a dry powder with a dry gelatin binder in an approximate weight ratio of 1:2. A trace amount of magnesium stearate is added as a lubricant. The mixture is formed into tablets of 0.3 - 30 mg (0.1 - 10 mg of the active compound per tablet) using a tableting machine.

[0106] Exemplary formulation 9 - tablets: The compound of formula (I - A), or a pharmaceutically acceptable salt thereof, can be mixed as a dry powder with a dry gelatin binder in an approximate weight ratio of 1:2. A trace amount of magnesium stearate is added as a lubricant. The mixture is formed into tablets of 150 - 240 mg (50 - 80 mg of the active compound per tablet) using a tableting machine.

[0107] Exemplary formulation 10 - tablets: The compound of formula (I - A), or a pharmaceutically acceptable salt thereof, can be mixed as a dry powder with a dry gelatin binder in an approximate weight ratio of 1:2. A trace amount of magnesium stearate is added as a lubricant. The mixture is formed into tablets of 270 - 450 mg (90 - 150 mg of the active compound per tablet) using a tableting machine.

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

[0109] For the prevention and / or treatment of long - term conditions, since the regimen is usually over several months or years, oral dosing is preferred for patient convenience and tolerance. In the case of oral administration, oral administration 1 - 5 times a day, particularly 2 - 4 times a day, typically 3 times a day, is a typical regimen. When using these dosing patterns, each dose results in from about 0.01 to about 20 mg / kg of the compounds provided herein, and preferred doses each result in from about 0.1 to about 10 mg / kg, particularly from about 1 to about 5 mg / kg.

[0110] Transdermal administration is generally selected to give 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, upon the advice and under the supervision of a physician, at the dosage levels described above, to subjects at risk of developing the symptoms. Subjects at risk of developing particular symptoms generally include subjects with a family history of the symptoms, or subjects identified by genetic testing or screening as being particularly susceptible to the development of the symptoms. Methods of treatment and uses

[0112] The compounds of the present invention (e.g., compounds of formula (I-A), (I-B), (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) are generally designed, as described herein, to modulate NMDA function and thus to 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 (I-A), (I-B), (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) are generally designed to cross the blood-brain barrier (e.g., designed to be transported across the blood-brain barrier). Modulate, as used herein, refers to, for example, inhibition or synergy of NMDA receptor function. In certain embodiments, a compound of formula (I-A), (I-B), (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 (NAM) of NMDA and can inhibit NMDA receptor function. In certain embodiments, the present invention (e.g., a compound of formula (I-A), (I-B), (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 (PAM) of NMDA and can synergize NMDA receptor function.In certain embodiments, a compound of formula (I-A), (I-B), (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), structural disorders affecting the GI, anal disorders (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas), colon polyps, cancer, colitis. In some embodiments, the disorder is inflammatory bowel disease. In some embodiments, the disorder is Smith-Lemli-Opitz syndrome (SLOS). In some embodiments, the disorder is desmosterolosis. In some embodiments, the disorder is sitosterolemia. In some embodiments, the disorder is cerebrotendinous xanthomatosis (CTX). In some embodiments, the disorder is mevalonate kinase deficiency (MKD). In some embodiments, the disorder is SC4MOL gene mutation (SMO deficiency). In some embodiments, the disorder is Niemann-Pick disease. In some embodiments, the disorder is autism spectrum disorder (ASD). In some embodiments, the disorder is related to phenylketonuria.

[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 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 related to 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, anorectal disorders (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas), colorectal polyps, cancer, colitis), as well as CNS conditions (e.g., those 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, cyclothymic disorder, suicidal tendency), schizophrenia or other psychotic disorders (including schizoaffective psychosis), sleep disorders (including insomnia), substance use-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations in Shank family proteins (e.g., Shank3)), neurodevelopmental disorders (including Rett syndrome), multiple sclerosis, steroid synthesis disorders, pain (including acute pain and chronic pain), seizure disorders (including status epilepticus and single-gene forms of epilepsy, e.g., Dravet disease, and tuberous sclerosis complex (TSC)), stroke, traumatic brain injury, movement disorders (including Huntington's disease and Parkinson's disease), and tinnitus, but are not limited thereto. In certain embodiments, the compounds of the invention (e.g., compounds of formula (I-A), (I-B), (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, the compounds of formula (I-A), (I-B), (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, are useful in the treatment or prevention of adjustment disorders, anxiety disorders, cognitive disorders, dissociative disorders, eating disorders, mood disorders, schizophrenia or other psychotic disorders, sleep disorders, substance-related disorders, personality disorders, autism spectrum disorders, neurodevelopmental disorders, steroid synthesis disorders, pain, seizure disorders, stroke, traumatic brain injury, movement disorders, and visual disorders, auditory disorders, and tinnitus.

[0117] In another aspect, there is provided a method for treating or preventing brain excitability in a subject suspected of or troubled by a condition associated with brain excitability, the method comprising administering to the subject an effective amount of a compound of the invention (e.g., a compound of formula (I-A), (I-B), (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).

[0118] In yet another aspect, there is provided a combination of a compound of the invention (e.g., a compound of formula (I-A), (I-B), (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 a single active agent or in combination with other agents. Administration in combination can proceed by any technique apparent to those skilled in the art (e.g., separate administration, sequential administration, simultaneous administration, and alternating administration). Diseases and Disorders Methods for treating sterol synthesis disorders are described herein. Exemplary disorders are described herein. The method comprises administering an NMDA receptor modulating compound to a subject, e.g., a subject suffering from a sterol synthesis disorder such as SLOS. Exemplary compounds are described herein. Sterol Synthesis Disorders

[0119] In one aspect, methods for treating sterol synthesis disorders are described herein. Cholesterol has essential roles in growth and development. Cholesterol is a membrane lipid and is also a precursor of many molecules that play important roles in cell growth and differentiation, protein glycosylation, and signaling pathways. The biosynthesis of cholesterol involves several enzymes and intermediates. Disorders resulting from deficiencies in any of the enzymes involved in cholesterol biosynthesis lead to the accumulation of intermediates and imbalance of biomolecules, resulting in disorders including congenital skeletal malformations, dysmorphic facial features, psychomotor retardation, and growth disorders. In certain embodiments, a sterol synthesis disorder or symptoms of a sterol synthesis disorder can be treated by administering to a subject suffering from the sterol synthesis disorder a compound described herein (e.g., an NMDA receptor modulating compound as described herein). Further 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 disorder of cholesterol synthesis. In addition to microcephaly, moderate to severe intellectual disability, hypersensitivity, stereotyped behaviors, dysmorphic facial features, and syndactyly of the second / third toes, this disorder is characterized by low levels of cerebrosterol (24(S)-hydroxycholesterol). SLOS is an autosomal recessive disorder resulting from a deficiency of the last enzyme in the cholesterol synthesis pathway, and causes low or low-normal plasma cholesterol levels and high levels of 7- and 8-dehydrocholesterol (DHC; 7DHC and 8DHC). Current common treatments 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 enhance 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, methods for treating desmosterolosis with the compounds described herein are 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 enhances the absorption of plant sterols and cholesterol from the intestine. Patients typically exhibit tendon xanthomas and tuberous xanthomas as well as 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, methods for treating cerebrotendinous xanthomatosis (also referred to as cerebral cholesterolosis or Van Bogaert - Scherer - Epstein syndrome) with the compounds described herein are described herein. CTX can be caused by mutations in the CYP27A1 gene that produces the sterol 27 - hydroxylase enzyme. Sterol 27 - hydroxylase metabolizes cholesterol into bile acids (e.g., chenodeoxycholic acid) that are important in the absorption of fat in the intestine. Dysfunction of the enzyme can lead to cholesterol accumulation in tissues. CTX is characterized by diarrhea in children, cataracts in adults, tendon xanthomas, reduced mental capability and abnormal movements. Mevalonate kinase deficiency syndrome (MKD)

[0124] Mevalonate kinase deficiency (also referred to as mevalonic aciduria (a more severe form of MKD), or hyper - IgD syndrome with periodic fever syndrome (HIDS i.e., hyperglobulinemia D) (a more benign form of MKD)) causes the accumulation of mevalonic acid in the urine as a result of insufficient activity of mevalonate kinase. MKD can result in growth retardation, hypotonia, anemia, hepatosplenomegaly, dysmorphic features, mental retardation and general growth impairment. Mevalonic aciduria is characterized by delays in physical and mental development, growth impairment, recurrent episodes of fever with vomiting and diarrhea, hypertrophy of the liver, spleen and lymph nodes, microcephaly (small head size), cataracts, hypotonia, short statute, distinctive facial features, ataxia and anemia. HIDS is characterized by recurrent episodes of fever with lymph node swelling, joint pain, gastrointestinal problems and rashes. In one aspect, methods for treating MKD with the compounds described herein are described herein. SC4MOL gene mutation (SMO deficiency)

[0125] SC4MOL gene deficiency is a genetic disorder in the cholesterol biosynthesis pathway (e.g., a mutation in the SC4MOL gene encoding a novel sterol oxidase). SC4MOL deficiency is characterized by the accumulation of dimethyl sterols and monomethyl sterols that can be detected in blood, skin biopsies, or primary skin fibroblasts. In one aspect, methods for treating SMO deficiency with the compounds described herein are described herein. Niemann-Pick disease

[0126] Niemann-Pick disease is a lysosomal storage disorder caused by a gene mutation that affects metabolism. Niemann-Pick disease results in the abnormal accumulation of cholesterol and other fatty substances (lipids) because the body cannot transport them, and this accumulation damages the affected areas. Autism

[0127] In one aspect, methods for treating an autism spectrum disorder or autism are described herein. Autism spectrum disorder (ASD) and autism refer to a group of complex disorders of brain development. Autism is typically characterized by difficulties with social interactions, such as communication by speech and non-speech communication. Individuals with autism often exhibit repetitive behaviors. Autism can be associated with 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, math, and art. Autism can refer to autistic disorder, childhood disintegrative disorder, pervasive developmental disorder not otherwise specified (PDD-NOS), and Asperger syndrome. Autism can also refer to single-gene cause autism, such as synaptopathies, such as Rett syndrome, Fragile X syndrome, Angelman syndrome. Disorders associated with phenylketonuria

[0128] In one aspect, methods for treating disorders associated with phenylketonuria (e.g., cognitive disorders) with the compounds described herein are described herein. Phenylketonuria can lead to hypocholesterolemia and low vitamin D status. Total cholesterol, low density cholesterol, and 25-hydroxyvitamin D were found to be decreased in subjects with phenylketonuria compared to subjects without phenylketonuria (Clin. Chim. Acta 2013, 416:54-59). 24S-hydroxy cholesterol, 27S-hydroxy cholesterol, and 7α-hydroxy cholesterol (e.g., representative of peripheral and hepatic cholesterol excretion, respectively) were shown to be significantly decreased in subjects with phenylketonuria, while 7β-hydroxy cholesterol (e.g., reflective of oxidative stress) was significantly increased in subjects with phenylketonuria. Changes in the levels of 24S-OHC and 7β-hydroxy cholesterol correlated with the levels of phenylalanine, and the level of 27S-hydroxy cholesterol may correlate with the level of 25-hydroxyvitamin D in subjects with phenylketonuria. Alternative embodiments In alternative embodiments, the compounds described herein (e.g., compounds of formula (I-A), (I-B), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J)) may also contain one or more isotope substitutions. In some embodiments, hydrogen may be 2 H (D i.e., deuterium), or 3 H (T i.e., tritium). In some embodiments, carbon may be 13 C or 14 C. In some embodiments, oxygen may be 18 O). In some embodiments, nitrogen may be 15It may also be N. In a further embodiment, the compound may contain one or more isotope substitutions, and the sites of isotope substitution are enriched with specific isotopes. For example, the compounds described herein may contain 2 H or 3 hydrogen enriched as 13 C or 14 carbon enriched as 18 oxygen enriched as 15 N, or nitrogen enriched as

Examples

[0129] For the purpose of enabling a more complete understanding of the invention described herein, the following examples are presented. The synthetic and biological examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein and should in no way be construed as limiting their scope. Materials and Methods

[0130] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Although typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it is understood that other process conditions can also be used unless otherwise stated. The optimal reaction conditions may vary depending on the specific reactants or solvents used, and such conditions can be determined by those skilled in the art through routine optimization.

[0131] Furthermore, as may 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 suitable protecting groups for specific functional groups, as well as the conditions suitable for protection and deprotection, are well known in the art. For example, numerous protecting groups and their introduction and removal are described in T.W. Greene and P.G.M. Wuts, 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 with respect to the preparation of representative pyrazoles listed herein. The compounds provided herein can be prepared by those skilled in the art of organic synthesis from known or commercially available starting materials and reagents. Exemplary chiral columns available for use in the separation / purification of enantiomers / diastereomers provided herein include, but are not limited to, CHIRALPAK® AD-10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ and CHIRALCEL® OK.

[0133] Exemplary general method for preparative HPLC: Column: Waters RBridge prep 10μm C18, 19×250mm. Mobile phase: acetonitrile, water (NH4HCO3) (30 L of water, 24 g of NH4HCO3, 30 mL of 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% - 95% B over 1.6 minutes or 2 minutes. Flow rate: 1.8 or 2 mL / min; Column: XBridge C18, 4.6×50 mm, 3.5 μm, 45°C. NMDA synergy

[0135] NMDA synergy was evaluated using whole-cell patch clamp of mammalian cells expressing the NMDA receptor. Whole-cell patch clamp of mammalian cells (Ionworks Barracuda (IWB) The effect of compounds on GluN1 / GluN2A glutamate receptors expressed in mammalian cells was investigated using whole-cell patch clamp technology. 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 maintaining the selection pressure with G418 and Zeocin in the medium. The cells were cultured in Dulbecco's modified Eagle medium / nutrient mixture (D-MEM / F-12) supplemented with 10% fetal bovine serum, 100 μg / ml penicillin G sodium, 100 μg / ml streptomycin sulfate, 100 μg / ml Zeocin, 5 μg / ml blasticidin, and 500 μg / ml G418. The effect of the test article was evaluated in an 8-point concentration-response format (4 replicates / concentration). All test solutions and control solutions contained 0.3% DMSO and 0.01% Kolliphor® EL (C5135, Sigma). The formulation of the test article was loaded into a 384-well compound plate using an automated liquid handling system (SciClone ALH3000, Caliper LifeScienses). Measurements were performed using the Ion Works Barracuda platform according to this procedure: Electrophysiological Procedure: a) Intracellular solution (mM): 50 mM CsCl, 90 mM CsF, 2 mM MgCl2, 5 mM EGTA, 10 mM HEPES. Adjusted to pH 7.2 with CsOH. b) Extracellular solution, HB-PS (composition in mM): NaCl, 137; KCl, 1.0; CaCl2, 5; HEPES, 10; glucose, 10; 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) The extracellular buffer is loaded into the PPC plate wells (11 μL per well). The cell suspension is pipetted into the wells of the PPC planar electrode (9 μL per well). b) The whole-cell recording configuration is established by patch perforation, and the membrane current is recorded by an on-board patch clamp amplifier. c) Two recordings (scans) are performed. The first is during the pre-amplification period of the test article alone (pre-amplification duration - 5 minutes), and the second is during the simultaneous application of the test article and agonist (EC 20 L-glutamate and 30 μM glycine) to detect the positive regulatory effect of the test article. Administration of the test article: The first pre-application consists of the addition of 20 μL of a 2-fold concentrated test article solution, and the second consists of the addition of 20 μL of a 1-fold concentration of the test article and agonist at 10 μL / s (total application time of 2 seconds).

[0136] Synthesis Method Example 1. Synthesis of Intermediate A-6.

Chemical Formula

[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, and then water (42 mL) was added. The mixture was stirred at 25 °C for 30 minutes. Water (1500 mL) and NaHCO3 (750 g) were added portionwise (evolution of gas was observed). The mixture was filtered through a pad of celite, and the solid was washed with DCM (500 mL). The organic layer in the filtrate was separated, washed with Na2S2O3 (1000 mL, saturated), dried over Na2SO4, filtered, and concentrated under reduced pressure below 30 °C to give Intermediate A-2 (250 g, crude) as a pale yellow gummy substance. This crude product was used directly in the next step without further purification or analysis.

[0138] Process 3. Synthesis of Intermediate A-3. To a solution of BHT (769 g, 3.49 mol) in toluene (1500 mL) was added AlMe3 (870 mL, 2 M in toluene, 1.74 mol) at 0 °C. After stirring at 0 °C for 1 h, the reaction mixture was cooled to -78 °C, and a solution of 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 an additional 1 h. The mixture was quenched by pouring it slowly into citric acid (4000 mL, 20% aqueous solution) (gas evolution was observed). Two other batches were carried out and combined. The mixture was extracted with EtOAc (10 L). The organic layer was separated, washed with brine (5 L, 10%), NaHCO3 (5 L, saturated aqueous solution), brine (5 L, saturated), dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (from PE to EtOAc) to give Intermediate A-3 (440 g, impure, containing Intermediate A-1) as a pale yellow solid. To a solution of impure Intermediate A-3 (440 g) in DCM (6 L) were added DMAP (24.4 g) and Ac2O (51 g). The mixture was stirred at 20 °C for 1 h. NaHCO3 (1 L, saturated aqueous solution) was added, and the mixture was stirred for 10 min. The organic layer was separated, concentrated under reduced pressure, and the residue was triturated with PE (2 L). The solid was washed with PE (3 × 500 mL) and dried under reduced pressure to give A-3 (262 g) as an off-white solid. The combined filtrates were 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%. 11H 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 back to 10 °C to generate an off - white precipitate. Ethanol (279 g, 6080 mmol) and aqueous NaOH (304 mL, 5 M, 1520 mmol) were added dropwise at < 10 °C to obtain a clear solution. Hydrogen peroxide (343 g, 30% in water, 3040 mmol) was added dropwise at < 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 under reduced pressure to obtain an off - white solid, which was triturated with refluxing ethanol (1.5 L) to obtain Intermediate A - 4 (92 g, 88%) as an off - white solid. 1 1H 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 h. 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 Na2SO4, 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 h. Sodium benzenesulfinate (195 g, 975 mmol) was added and stirring was continued at 60 °C for 2 h. 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 Na2SO4, filtered, and concentrated under reduced pressure to give a yellow solid residue, which was recrystallized from toluene (2.5 L) to give Intermediate A-6 (150 g, 65%) as a bright yellow solid. The recrystallization filtrate was concentrated under reduced pressure to give crude Intermediate A-6 (30 g) as a yellow solid. 1 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 7.2 Hz, 2H), 7.69-7.61 (m, 1H), 7.60-7.50 (m, 2H), 5.28-5.27 (m, 1H), 3.14 (d, J = 14.0 Hz, 1H), 2.85 (dd, J = 9.6, 14.0 Hz, 1H), 2.41 (d, J = 12.8 Hz, 1H), 2.17-2.03 (m, 1H), 2.02-1.87 (m, 3H), 1.81-1.65 (m, 3H), 1.60-1.32 (m, 8H), 1.25-0.85 (m, 15H), 0.65 (s, 3H). LCMS Rt = 2.057 min, 30 - 90 AB, MS ESI C 29 H 41 O2S [M+H-H2O] + Calculated for 453, found 453.

[0142] Example 2. Synthesis of Intermediate B-4. [Chemical Structure] 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 h. 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 h. EtMgBr (141 mL, 426 mmol) was added at -78 °C, and the mixture was stirred at -78 °C for 20 min. Saturated citric acid (1 L) was added. The organic phase was separated, washed with brine (600 mL), dried over Na2SO4, and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (PE:EtOAc = 50:1~30:1) 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 mmol) was added Intermediate B-1 (13 g, 37.9 mmol) at 0 °C under N2. 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 H2O2 (57 g, 30% in water), and the resulting mixture was stirred at 75 °C for 1 h. The mixture was concentrated under reduced pressure 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 under reduced pressure to give a residue, which was purified by column chromatography on silica gel (PE:EtOAc = 50:1~3:1) to give Intermediate B-2 (9.86 g, 72%) as an off-white solid. 1 1H 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] Project 3. Synthesis of Intermediate B-3. To a solution of Intermediate B-2 (9.86 g, 27.3 mmol) in CHCl3 (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 h. The reaction mixture was concentrated under reduced pressure to give a 60 mL 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 Na2SO4, filtered, and concentrated under reduced pressure to give Intermediate B-3 as an off-white solid (9.9 g, 70%). 1 1H 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] Process 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 Na2SO4, filtered, and concentrated under reduced pressure to give a yellow solid residue, which was purified by silica gel chromatography (0 - 35% EtOAc in PE) to afford 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.

Chemical Structure

[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 N2 for 1 h (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 H2O2 (3.94 L, 10 M, 39.4 mol) at 25 °C (the internal temperature rose until reflux). After the addition was complete, the mixture was cooled to 25 °C and stirred for 16 h, then Na2SO3 (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 give a clear lower layer and an upper suspension layer. The upper suspension layer was collected and treated with water (20 L). The mixture was stirred for 15 min and filtered. The solid was washed with water until the pH was <9 to give the wet product, which was combined with the products from two other batches 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] Process 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) were added N-methyl-imidazole (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 above solution while maintaining the internal temperature at 25 - 30 °C. The reaction mixture was stirred at 25 °C for 1 hour. To this mixture were added water (10 L), citric acid (20%, 1 L) and HCl (1 M) to adjust the pH to about 3. The organic layer was separated, washed with water (2×10 L), saturated aqueous NaHCO3 (5 L) and brine (5 L), dried over Na2SO4, filtered, and concentrated to obtain 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 h. PhSO2Na (2.19 kg, 13.4 mol) was added, and stirring was continued at 70 °C for 1 h. The mixture was poured into water (50 L) and filtered. The filter cake was washed with water (2 × 10 L) to give the 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 under reduced pressure to give Intermediate C-4 (2.21 kg) as a white solid. The other 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. In total, 4.13 kg of product was obtained (67% yield). 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 h to obtain a clear solution, which was treated with water (25 L) and stirred at 80 °C for 2 h. After cooling, the mixture was filtered and the filter cake was washed with water (3 × 10 L) and air-dried to obtain Intermediate C-5 (1.83 kg, crude) as an off-white solid. 1 1H 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 three times with N2, the reaction mixture was purged three times with H2. The reaction mixture was stirred at 25 °C for 72 h under a hydrogen atmosphere (50 Psi). The formation of the desired product and the consumption of the starting material were confirmed by NMR. The catalyst was removed by filtration and the filtrate was concentrated to obtain Intermediate C-6 (39 g, crude) as an off-white solid, which was used directly in the next step without further purification. 11H 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 under reduced pressure to give a residue, which was purified by silica gel chromatography (DCM) to give Intermediate C-7 (145 g, 74%) as an off-white solid. 1 1H 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) was added dropwise trimethylaluminum (2 M in toluene, 525 mL, 1.05 mmol) at 0 °C under N2. The mixture was stirred at 25 °C for 1 h and then 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 h. Ethylmagnesium 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 h. The reaction mixture was quenched with saturated citric acid (2 L) at -70 °C, warmed slowly to 25 °C, and extracted with ethyl acetate (500 mL × 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0% - 30% EtOAc in PE) to give Intermediate C-8 (153 g, 90%) as an off-white solid. A small sample (300 mg) of this material 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 Chromatography for 2.0 min, Rt = 1.194 min, 30 - 90 AB, purity 100%, MS ESI C 30 H48 O4S[M+H2O] + Calculated value 504 and measured value 504 for it.

[0154] Example 4. Synthesis of Compound 1.

Chemical formula

[0155] Step 2. Synthesis of Intermediate 1-3. To a flask containing THF (5 mL), n-BuLi (2.5 M, 1.59 mmol, 0.636 mL) was added at -70 °C under N2. A suspension of A-6 (0.637 mmol, 300 mg) in THF (4 mL) was added dropwise to obtain a bright yellow suspension. After stirring at -70 °C for 30 minutes, 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 hours. 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 bright yellow solid, which was used directly in the next step.

[0156] Procedure 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 h. The reaction was quenched with HCl (50 mL, 1 N) and extracted with DCM (2 × 30 mL). The combined organic phases were dried over Na2SO4, filtered, concentrated, and the residue was purified by silica gel chromatography (0 - 10% EtOAc in PE) to give 50 mg of impure product, which was further purified by SFC (column: AD (250 mm × 30 mm, 5 μm), gradient: 0 - 40% B (A = 0.05% NH3 / H2O, B = MeOH); flow rate (mL / min): 60) to give Compound 1 (32 mg, 10%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) 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 chromatography at 2.0 min with Rt = 1.256 min, 30 - 90 AB_ELSD, purity 100%, MS ESI C 30 H 45 F2[M + H - 2H2O] + Calculated value for 443, found value 443.

[0157] Example 5. Synthesis of Compound 2.

Chemical Structure

[0158] Step 2. Synthesis of Intermediate 2-3. To a flask containing THF (4 mL) was added n-BuLi (2.5 M, 3.17 mmol, 1.26 mL, 2.5 equiv) at -70 °C under N2, and then a suspension of A-6 (600 mg, 1.27 mmol) in THF (6 mL) was added dropwise. 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 Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 5 / 1) to give Intermediate 2-3 (400 mg, impure) as a bright yellow solid. LCMS chromatography at 1.5 min with Rt = 1.066 min, 5 - 95 AB, MS ESI C 36 H 53 O3S [M + H - H2O] + Calculated value for 565, found value 565.

[0159] Procedure 3. Synthesis of Compound 2. To a solution of Intermediate 2-3 (400 mg, 0.69 mmol) in 10 mL of dry methanol was added magnesium turnings (492 mg, 20.5 mmol) (activated with 0.5% aqueous HCl, water, dry ethanol, and MTBE) and NiCl2 (44.4 mg, 0.34 mmol) under N2 nitrogen, and the reaction was stirred at 50 °C for 1 h. The reaction was quenched by adding 2 M HCl (50 mL) dropwise at 10 °C until all solids were completely dissolved. The mixture was extracted with EtOAc (50 mL), and the organic layer was washed with saturated NaHCO3 (50 mL), brine (50 mL), dried over Na2SO4, 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 chromatography at 2.0 min with Rt = 1.353 min, 30 - 90 AB, MS ESI C 30 H 47 [M + H - 2H2O] + Calculated value for 407, found 407.

[0160] Example 6. Synthesis of Compound 3.

Chemical formula

[0161] Step 2. Synthesis of Intermediate 3-3. To a flask containing THF (4 mL) was added n-BuLi (2.5 M, 5.30 mmol, 2.11 mL) at -70 °C under N2, and then a suspension of A-6 (2.12 mmol, 1 g) in THF (10 mL) was added dropwise. 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 phases were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give Intermediate 3-3 (1.2 g, crude) as a yellow solid. LCMS chromatography at 2.0 minutes with Rt = 1.161 minutes and 1.222 minutes, 30 - 90 AB, 28%, MS ESI C 35 H 52 O4SNa [M+Na] + Calculated value for 591, found value 591.

[0162] Procedure 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 mmol) (activated with 0.5% aqueous HCl, water, dry ethanol, and MTBE) and NiCl2 (54.4 mg, 0.42 mmol) were added under N2 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 layers were washed with saturated NaHCO3 (500 mL), brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 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. This 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 the product. This product was washed with n-hexane (5 mL) to obtain 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 Chromatography at 2.0 minutes with Rt = 1.161 minutes and 1.295 minutes, 30 - 90 AB_E, MS ESI C 29 H 45 [M + H - 2H2O] + Calculated value for 393, found 393.

[0163] Example 7. Synthesis of Compound 4.

Chemical Structure

[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) was added A-6 (500 mg, 1.06 mmol) at -78 °C under nitrogen, 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 above 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 obtain Intermediate 4-3 (100 mg, 17%) as an off-white solid. LCMS chromatography for 2.0 minutes, Rt = 1.131 minutes, 30 - 90 AB, MS ESI C 34 H 49 O3S [M + H - H2O] + Calculated value for 537, measured value 537.

[0165] Procedure 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 h, cooled to room temperature, neutralized with 1 M HCl, and extracted with EtOAc (4 × 20 mL). The combined organic layers were 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, which was triturated with n-hexane to afford 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 chromatography for 2.0 minutes, Rt = 1.230 min, 30 - 90 AB, MS ESI C 28 H 43 [M + H - 2H2O] + Calculated value for 379, found 379.

[0166] Example 8. Synthesis of Compound 5.

Chemical Structure

[0167] Step 2. Synthesis of Intermediate 5-3. To a flask containing THF (2 mL) was added n-BuLi (0.9 mL, 2.22 mmol, 2.5 M) at -78 °C under N2, and then A- A suspension of 6 (300 mg, 0.637 mmol) in THF (4 mL) was added to give a pale yellow suspension. After stirring at -78 °C for 30 minutes, 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 minutes and at 15 °C for 16 hours. 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 chromatography for 1.5 minutes, Rt = 0.907 minutes, 5~95 AB, MS ESI C 34 H 49 O4S [M+H-H2O] + Calculated value for 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, 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 under N2 to initiate continuous hydrogen evolution. After adding 4 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 phases were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0%~50% EtOAc in PE) to give compound 5 (34 mg, 15%) as an off-white solid. 11H 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 retention time (Rt) = 1.111 min in a 2 - minute chromatography run, 30 - 90 AB_E, MS ESI C 30 H 49 O3NNa [M + MeCN + Na] + Calculated value for [M + MeCN + Na] is 494, found value is 494.

[0169] Example 9. Preparation of Compounds 5 - A and 5 - B

Chemical Structure

[0170] Compound 5 - A 1 1H 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 chromatography for 2 minutes, Rt = 1.091 minutes, 30 - 90 AB_E, purity 100%, MS ESI C 28 H 46 O3Na [M+Na] + Calculated value for it is 453, measured value is 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 chromatography for 2 minutes, Rt = 1.093 minutes, 30 - 90 AB_E, purity 100%, MS ESI C 28 H 43 O [M+H - 2H2O] + Calculated value for it is 395, measured value is 395.

[0172] Example 10. Synthesis of Compound 6.

Chemical Structure

[0173] Process 2. Synthesis of Intermediate 6-3. To a flask containing THF (5 mL) was added n-BuLi (2.96 mL, 7.42 mmol, 2.5 M) at -78 °C under N2, and then a suspension of A-6 (1 g, 2.12 mmol) in THF (10 mL) was added dropwise to obtain a pale yellow suspension. After stirring at -78 °C for 30 minutes, 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 minutes and at 15 °C for 16 hours. The reaction was quenched with saturated NH4Cl (50 mL) and extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give crude Intermediate 6-3 (1 g) as a yellow solid, which was used directly in the next step. LCMS Rt = 2.423 minutes by 3.0-minute chromatography, 10 - 80 AB, MS ESI C 35 H52 O5SNa [M+Na] + Calculated value 607 and measured value 607 for

[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, anhydrous 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 4 batches of magnesium turnings (410 mg in 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 phases were washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (0% - 70% EtOAc in PE) to obtain 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 retention time = 2.043 min for 3.0 minutes of chromatography, 10 - 80 AB, MS ESI C chromatography, MS ESI C 29 H 45 O [M+H - 2H2O] + Calculated value 409 and measured value 409 for

[0175] Example 11. Synthesis of Compound 7.

Chemical Structure

[0176] Step 2. Synthesis of Intermediate 7-3. To a solution of n-BuLi (2.5 M in hexanes, 4.2 mL, 10.6 mmol) in anhydrous THF (20 mL) was added A-6 (2 g, 4.24 mmol) at once at -70 °C under nitrogen, 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 warmed gradually 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 afford Intermediate 7-3 (2.3 g, 79%) as an off-white solid. 11H 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) was added magnesium turnings (3.25 g, 134 mmol) portionwise at 45 °C under nitrogen. 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 NaHCO3 (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (PE:THF = 6:1) to afford Intermediate 7 - 4 (1.1 g, 60%) as an off - white solid. 1 1H 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) were 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 h. The precipitated solid was collected by filtration and dried under reduced pressure to give the crude product (720 mg), which was triturated with methanol to afford 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 chromatography at 2.0 minutes gave Rt = 1.054 min, 10-80 AB, MS ESI C 29 H 50 NO2[M+H] + Calculated value for 444, found 444.

[0179] Example 12. Synthesis of Compound 8.

Chem.

[0180] Example 13. Synthesis of compound 9.

Chemical Structure

[0181] Example 14. Synthesis of Compound 10.

Chemical Structure

[0182] Step 2. Synthesis of Intermediate 10-3. To a flask containing THF (0.5 mL) was added n-BuLi (1.05 mL, 2.5 M, 2.65 mmol) at -70 °C under N2, and then a suspension of Intermediate A-6 (500 mg, 1.06 mmol) in THF (1 mL) was added dropwise to obtain a bright 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 mixture 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] Procedure 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 N2, magnesium powder (794 mg, 32.7 mmol) was added 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 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 NaHCO3 (300 mL), brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 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 um)), gradient: 55 - 55% B (A = 0.1% NH3 / H2O, B = EtOH), flow rate: 80 mL / min) to give Compound 10 (39 mg) as an off-white solid. 1 1H 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 Chromatography for 2.0 minutes, Rt = 1.481 minutes, 30 - 90 AB, purity 100%, MS ESI C 32 H 51 [M + H - 2H2O] - Calculated value for 435, measured value 435.

[0184] Example 15. Synthesis of Compound 11.

Chemical Structure

[0185] Step 2. Synthesis of Intermediate 11-3. To a flask containing THF (3 mL) was added n-BuLi (1.48 mL, 3.71 mmol, 2.5 M) at -78 °C under N2, and then a suspension of Intermediate A-6 (500 mg, 1.06 mmol) in THF (5 mL) was added dropwise to obtain a pale yellow suspension. After stirring at -78 °C for 30 min, 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 min and at 15 °C for 16 h. The reaction was quenched with aqueous NH4Cl (50 mL) and extracted with EtOAc (3 × 30 mL). The combined organic phases were 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 Chromatography at 1.5 min, Rt = 0.939 min, 5 - 95 AB, purity 79%, MS ESI C35 H 51 O4S [M+H - H2O] + Calculated value for it is 567, measured value is 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 phases were washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (0% - 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 Chromatography for 2 minutes, Rt = 1.226 minutes, 30 - 90 AB_E, purity 100%, MS ESI C 29 H 45 O [M+H - 2H2O] +Calculated value 409 and measured value 409 for

[0187] Example 16. Synthesis of Compound 12. [Chemical formula] 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 then 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 hour, and then treated at -70 °C with a solution of Intermediate 1-2 (1.89 g, 6.18 mmol, purity 50%) in THF (5 mL). The reaction was warmed to 25 °C and stirred for 16 hours. 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 obtain 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] Procedure 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, 1 N) until the reaction mixture became clear, and the resulting solution was extracted with DCM (2 × 30 mL). The combined organic phases were dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (0 - 10% EtOAc in PE) to afford 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 Chromatography for 2.0 min, Rt = 1.268 min, 30 - 90 AB, purity 100%, MS ESI C 31 H 47 F2[M + H - 2H2O] + Calculated value for 457, found 457.

[0189] Example 17. Synthesis of Compound 13.

Chemical Structure

[0190] Procedure 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. NiCl2 (34.2 mg, 268 μmol) and Mg powder (1.28 g, 53.6 mmol) were added at once, 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 Na2SO4, 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. 11H 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 chromatography for 2 minutes, Rt = 1.475 minutes, 30 - 90 AB, purity 100%, MS ESI C 33 H 53 [M + H - 2H2O] + Calculated value for 449, measured value 449.

[0191] Example 18. Synthesis of Compound 14.

Chemical Structure

[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 phases were washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (0% - 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 Chromatography for 2.0 minutes, Rt = 1.227 minutes, 30 - 90 AB, purity 100%, MS ESI C 30 H 47 O [M+H - 2H2O] + Calculated value 423, measured value 423 for

[0193] Example 19. Synthesis of Compound 15. [Chemical formula] Step 1. Synthesis of Intermediate 15-1. To a flask containing THF (3 mL), under N2 at -78 °C, n-BuLi (1.44 mL, 3.60 mmol, 2.5 M) was added, and then a suspension of Intermediate B-4 (500 mg, 1.03 mmol) in THF (5 mL) was added dropwise to obtain a light yellow suspension. After stirring at -78 °C for 30 minutes, a solution of Intermediate 11-2 (352 mg, 3.09 mmol) in THF (2 mL) was added. The reaction mixture 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 DCM (3 × 50 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude Intermediate 15-1 (500 mg) as a yellow solid, which was used directly in the next step. LCMS Chromatography for 1.5 minutes, Rt = 0.973 minutes, 5 - 95 AB, purity 47%, MS ESI C 36 H 53 O4S [M + H - H2O] + Calculated value for 581, measured value 581.

[0194] Procedure 2. Synthesis of Compound 15. To a solution of Intermediate 15-1 (500 mg, 0.834 mmol) in 20 mL of dry MeOH, 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 under N2 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 phases were washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (0% - 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 Chromatography for 2.0 minutes, Rt = 1.284 minutes, 30 - 90 AB, purity 100%, MS ESI C 30 H 47 O [M + H - 2H2O] + Calculated value for 423, found 423.

[0195] Example 20. Synthesis of Compound 16.

Chemical Structure

[0196] Example 21. Synthesis of Compound 17.

Chemical Structure

[0197] Example 22. Synthesis of Compound 18.

Chemical Structure

[0198] Example 23. Synthesis of Compound 19.

Chemical Structure

[0199] Example 24. Synthesis of Compound 20. [Chemical formula] 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) was added AlMe3 (16.3 mL, 32.7 mmol, 2 M in toluene) 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 this 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 dropwise at -65 °C and the resulting solution was stirred at -65 °C for 1 hour. The reaction was quenched with saturated aqueous NH4Cl solution (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 under reduced pressure to obtain 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) at -65 °C under N2 was added dropwise a suspension of Intermediate 20-1 (200 mg, 0.423 mmol) in THF (3 mL). After stirring at -65 °C for 30 minutes, a solution of diisopropylamine (127 mg, 1.26 mmol) was added dropwise, and then a solution of Intermediate 10-2 (176 mg, 1.26 mmol) was added dropwise. The mixture was stirred at -65 °C for an additional 30 minutes, then gradually warmed to 25 °C and stirred for 16 hours. The reaction was quenched with saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over Na2SO4, 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 NiCl2 (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 hour, 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 Na2SO4, filtered, concentrated, and purified by silica gel chromatography (0 - 20% EtOAc in PE) to give Compound 20 (100 mg, 48%). This 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). In LCMS chromatography for 2 minutes, Rt = 1.442 minutes, 30 - 90AB_2MIN_E, purity 100%, MS ESI C 32 H 53 [M + H - 2H2O] + The calculated value for it is 437, and the measured value is 437.

[0202] Example 25. Synthesis of Compound 21.

Chemical Structure

[0203] Procedure 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 then heated to reflux for 1 h. The reaction was quenched with HCl (50 mL, 1 N), and the resulting clear solution was extracted with DCM (2 × 30 mL). The combined organic phases were dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (0 - 10% EtOAc in PE) to give impure Compound 21 (120 mg, 44% yield, containing 22,23-olefin) as an off-white solid. This 120 mg of impure sample was dissolved in THF (5 mL) and treated with Pd / C (100 mg, wet). The mixture was hydrogenated for 2 h (15 Psi, 25 °C), 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 1H 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 Chromatography for 2.0 min, Rt = 1.325 min, 30 - 90 AB, purity 100%, MS ESI C 31 H 49 F2[M + H - 2H2O] + Calculated value for 459, found value 459.

[0204] Example 26. Synthesis of Compound 22.

Chemical Structure

[0205] Example 27. Synthesis of compound 23.

Chemical Structure

[0206] Example 28. Synthesis of compound 24.

Chemical Structure

[0207]

Table 1 - 1

Table 1 - 2

[0208] The data in Table 1 demonstrate the ability of the exemplary compound to modulate the NMDA receptor as a positive allosteric modulator (PAM). Other embodiments

[0209] In the claims, the articles (e.g., "a", "an", and "the") can mean one or more unless the contrary is indicated or is not apparent from the context. Unless the contrary is indicated or is not apparent from the context, a group A claim or description that includes "or" among one or more members is considered to satisfy that one, more than one, or all of the group members are present in, used in, or otherwise related to a given product or process. The present invention includes embodiments in which exactly one member of the group is present in, used in, or otherwise related to a given product or process. The present invention also includes embodiments in which more than one or all of the group members are present in, used in, or otherwise related 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 recited claims are introduced into another claim. For example, any claim that depends on another claim can be modified to include one or more limitations found in any other claim that depends on the same basic claim. When an element is presented as a list, for example, in the form of a Markush group, each subgroup of that element is also disclosed, and any element can be removed from that group. Generally, when the present invention or an aspect of the present invention is referred to as including a particular element and / or feature, a particular embodiment of the present invention or an aspect of the present invention should be understood to consist of or consist essentially of such element and / or feature. For simplicity purposes, those embodiments are not explicitly shown herein in such words. It should also be noted that the terms "comprising" and "containing" are intended to be open and allow for the inclusion of further elements or steps. When a range is given, the endpoints are included. Further, unless otherwise indicated or otherwise apparent from the context and the understanding of one of ordinary skill in the art, a value expressed as a range can be assumed to be any specific value or subrange within the recited range in various embodiments of the present invention to one tenth of the unit of the lower limit of that range, unless the context clearly indicates otherwise.

[0211] This application refers to various issued patents, published patent applications, academic papers, and other publications (all of which are incorporated herein by reference). If there is a conflict between any of the incorporated references and this specification, this specification shall govern. Further, any particular embodiment of the invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Such embodiments are considered to be known to those skilled in the art, so they may be excluded even if the exclusion is not explicitly shown in this specification. Any particular embodiment of the invention may be excluded from any claim for any reason, regardless of whether it is related to the existence of the prior art.

[0212] Those skilled in the art can recognize or confirm many equivalents to the specific embodiments described herein using only conventional experimental methods. The scope of the embodiments described herein is not intended to be limited to the above description, but rather as shown in the appended claims. Those skilled in the art recognize that various changes and modifications can be made to this description 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 (I-A):

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chemical formula

Chemical formula

Chemical formula

Claims

1. A compound having the structure of formula (A-6) 【Chemical Formula 1】

2. A compound having the structure of formula (B-4) 【Chemical Formula 2】

3. A compound having the structure of formula (C-8) 【Chemical Formula 3】

4. A process for preparing the compound according to Claim 1, comprising: a) reacting a compound having the structure 【Chemical Formula 4-1】 with a first reagent to provide a compound having the structure of formula (A-1) 【Chemical Formula 4-2】 ; b) reacting the compound of formula (A-1) with a second reagent to provide a compound of formula (A-2) 【Chemical Formula 4-3】 ; c) reacting the compound of formula (A-2) with a third reagent to provide a compound of formula (A-3) 【Chemical Formula 4-4】 ; d) reacting the compound of formula (A-3) with a fourth reagent and a fifth reagent to provide a compound of formula (A-4) 【Chemical Formula 4-5】 ; e) reacting the compound of formula (A-4) with a sixth reagent to provide a compound of formula (A-5) 【Chemical Formula 4-6】 ; and f) reacting the compound of formula (A-5) with a seventh reagent to provide a compound of formula (A-6) 【Chemical Formula 4-7】 The step of providing a compound of A process comprising

5. The process according to claim 4, wherein the first reagent is MePPH₃Br.

6. The process according to claim 4 or 5, wherein the second reagent is Dess-Martin periodinane.

7. The process according to any one of claims 4 to 6, wherein the third reagent is MeMgBr.

8. The process according to any one of claims 4 to 7, wherein step c) further comprises the use of 2,6-di-tert-butyl-4-methylphenol and AlMe₃.

9. The process according to any one of claims 4 to 8, wherein the fourth reagent is 9-borabicyclo[3.3.1]nonane and the fifth reagent is H₂O₂.

10. The process according to any one of claims 4 to 9, wherein the sixth reagent is tosyl chloride.

11. The process according to any one of claims 4 to 10, wherein the seventh reagent is sodium benzenesulfinate.

12. A process for preparing the compound according to claim 2, comprising a) Reacting a compound of formula (A-2) 【Chemical formula 12-1】 with a first reagent to provide a compound of formula (B-1) 【Chemical formula 12-2】 ; b) Reacting the compound of formula (B-1) with a second reagent and a third reagent to provide a compound of formula (B-2) 【Chemical formula 12-3】 ; c) Reacting the compound of formula (B-2) with a fourth reagent to provide a compound of formula (B-3) 【Chemical formula 12-4】 ; and d) reacting the compound of formula (B-3) with a fifth reagent to provide a compound of formula (B-4) [Chemical Formula 12-5] the step of providing a compound of A process comprising

13. The process according to claim 12, wherein the first reagent is EtMgBr.

14. The process according to claim 12 or 13, wherein step a) further comprises the use of 2,6-di-tert-butyl-4-methylphenol and AlMe3.

15. The process according to any one of claims 12 to 14, wherein the second reagent is 9-borabicyclo[3.3.1]nonane and the third reagent is H2O2.

16. The process according to any one of claims 12 to 15, wherein the fourth reagent is tosyl chloride.

17. The process according to any one of claims 12 to 16, wherein the fifth reagent is sodium benzenesulfinate.

18. A process for preparing the compound according to claim 3, comprising a) a compound of formula (A-1) [Chemical Formula 18-1] reacting the compound with a first reagent to provide a compound of formula (C-1) [Chemical Formula 18-2] the step of providing a compound of b) reacting the compound of formula (C-1) with a second reagent and a third reagent to provide a compound of formula (C-2) [Chemical Formula 18-3] the step of providing a compound of c) reacting the compound of formula (C-2) with a fourth reagent to provide a compound of formula (C-3) [Chemical Formula 18-4] the step of providing a compound of d) reacting the compound of formula (C-3) with a fifth reagent to provide a compound of formula (C-4) 【Chemical Formula 18-5】 A step of providing a compound of; e) Reacting the compound of formula (C-4) with a sixth reagent to obtain a compound of formula (C-5) 【Chemical Formula 18-6】 A step of providing a compound of; f) Reacting the compound of formula (C-5) with a seventh reagent and an eighth reagent to obtain a compound of formula (C-6) 【Chemical Formula 18-7】 A step of providing a compound of; g) Reacting the compound of formula (C-6) with a ninth reagent to obtain a compound of formula (C-7) 【Chemical Formula 18-8】 A step of providing a compound of; and h) Reacting the compound of formula (C-7) with a tenth reagent to obtain a compound of formula (C-8) 【Chemical Formula 18-9】 A step of providing a compound of A process comprising

19. The process according to claim 18, wherein the first reagent is tert-butyldimethylsilyl chloride.

20. The process according to claim 18 or 19, wherein the second reagent is 9-borabicyclo[3.3.1]nonane and the third reagent is H2O2.

21. The process according to any one of claims 18 to 20, wherein the fourth reagent is tosyl chloride.

22. The process according to any one of claims 18 to 21, wherein the fifth reagent is sodium benzenesulfinate.

23. The process according to any one of claims 18 to 22, wherein the sixth reagent is tetra-n-butylammonium fluoride. **Claim 24**: The process according to any one of claims 18 to 23, wherein the seventh reagent is palladium on carbon and the eighth reagent is H₂. **Claim 25**: The process according to any one of claims 18 to 24, wherein the ninth reagent is pyridinium chlorochromate. **Claim 26**: The process according to any one of claims 18 to 25, wherein the tenth reagent is EtMgBr. **Claim 27**: The process according to any one of claims 18 to 26, wherein step h) further comprises the use of 2,6-di-tert-butyl-4-methylphenol and AlMe₃.

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