Methods using C7-substituted oxysterols and NMDA modulators

Abstract

To provide a substituted oxysterol useful for preventing and / or treating a wide range of disorders. [Solution] Formula (A): Compounds of TIFF2026116412000235.tif2445, their pharmaceutically acceptable salts, and their pharmaceutically acceptable compositions are provided, in which R 1A , R 1B , n, R 2A , R 2B , R 3 and R 4 The compounds of the present invention are intended to be useful for the prevention and treatment of a variety of conditions. Substituted oxysterols useful for preventing and / or treating a wide range of disorders (including, but not limited to, NMDA-mediated disorders) are provided herein. Furthermore, pharmaceutical compositions containing the compounds of the present invention, as well as methods for their use and treatment, are provided.

Description

[Technical Field]

[0001] Related applications This application claims priority and benefit to U.S. Provisional Application No. 62 / 402,789 and U.S. Provisional Application No. 62 / 402,797, filed on September 30, 2016, and each of these U.S. Provisional Applications in their entirety is incorporated herein by reference. [Background technology]

[0002] Background of the Invention The NMDA receptor is a heteromeric complex containing NR1, NR2, and / or NR3 subunits, possessing distinct recognition sites for exogenous and endogenous ligands. These recognition sites include binding sites for glycine, as well as glutamate agonists and modulators. NMDA receptors are expressed in peripheral tissues and the CNS, where they are involved in excitatory synaptic transmission. Activation of these receptors contributes to synaptic plasticity in some situations and excitotoxicity in others. These receptors bind glutamate and glycine to Ca2+150. 2+ It is a ligand-gated ion channel that accepts glutamatergic signals and is fundamental to excitatory neurotransmission and normal CNS function. Positive modulators may be useful as cognitive enhancers and as therapeutic agents with potential clinical applications in the treatment of psychiatric disorders in which glutamatergic transmission is reduced or deficient (see, e.g., Horak et al., J. of Neuroscience, 2004, 24(46), 10318-10325). In contrast, negative modulators may be useful as therapeutic agents with potential clinical applications in the treatment of psychiatric disorders in which glutamatergic transmission is pathologically increased (e.g., treatment-resistant depression). Oxysterols are cholesterol analogs that modulator NMDA receptor function. Novel oxysterols that modulate NMDA receptors are needed for the prevention and treatment of conditions related to NMDA expression and function. The compounds, compositions, and methods described herein are directed toward this purpose. [Prior art documents] [Non-patent literature]

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

[0004] Summary of the Invention This specification provides substituted oxysterols useful for preventing and / or treating a wide range of disorders (including, but not limited to, NMDA-mediated disorders). Furthermore, pharmaceutical compositions containing the compounds of the present invention, as well as methods for their use and treatment, are provided.

[0005] In one phase, equation (A): [ka] Compounds or pharmaceutically acceptable salts thereof are provided herein, in which formula (A): R 1A and R 1B Each of them independently is hydrogen, a substituted or unsubstituted alkyl, a carbocykryl, a heterocyclyl, an aryl or heteroaryl, or R 1A and R 1B They form a 3- to 8-membered ring together with the carbon atoms to which they are bonded; n is either 1 or 2; R 2A and R 2B Each of these is independently hydrogen, halo, -OR C, alkyl, alkenyl, alkynyl, aryl or heteroaryl, where R C is hydrogen or alkyl, or R 2A and R 2B together with the carbon atom to which they are attached form an oxo group, where R 2A and R 2B are not both hydrogen at the same time; R 3 is hydrogen, alkyl, alkenyl, alkynyl or -OR A where R A is alkyl; R 4 is absent or is hydrogen; and

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0006] In some embodiments, n is 1. In other embodiments, n is 2.

[0007] In some embodiments, R 1A , R 3 and R 4 are hydrogen, and R 1B ​​​If R is an unsubstituted isopropyl, 2A and R 2B They do not form an oxo group with the carbon atoms to which they are bonded; and R 4 R does not exist, 3 is hydrogen, and R 1A and R 1B If R is -CH3, 2A It is not -CH3, and R 2B is not -OH. In a further embodiment, n is 1.

[0008] In some embodiments, R 4 R does not exist, 2A is -OH, and R 2B is hydrogen or -CF3, and R 1A and R 1B If R is -CH3, 3 It is not hydrogen; and R 1A and R 1B is -CH3, and R 3 If R is hydrogen, 2A and R 2B They do not form an oxo group with the carbon atoms to which they are bonded. Further embodiments In this case, n is 2.

[0009] In some embodiments, the compound of formula (A) is formula (AI): [ka] It is a compound of [the compound].

[0010] In some embodiments, the compound of formula (A) is of formula (A-II): [ka] It is a compound of [the compound].

[0011] In some embodiments, compounds of formula (A) are of formula (A-III): [ka] It is a compound of [the compound].

[0012] In some embodiments, the compound of formula (A) is (A-IV), (AV), or (A-VI): [ka] [In the formula, R 2C is hydrogen or alkyl, and R 3 Alkyl, alkenyl, Alkinyl or -OR A And here, R A It is an alkyl compound.

[0013] In some embodiments, compounds of formula (A) are of formulas (A-VII), (A-VIII), or (A-IX): [ka] [In the formula, R 3 is alkyl, alkenyl, alkynyl or -OR A And here, R A It is an alkyl compound.

[0014] In some embodiments, the compound of formula (A) is of formula (AX): [ka] [In the formula, R 3 is alkyl, alkenyl, alkynyl or -OR A And here, R A It is an alkyl compound.

[0015] In some embodiments, the compound of formula (A) is of formula (A-XII) [ka] [In the formula, R' is alkyl or -ORA And here, R A It is a compound of [where is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, or 3].

[0016] In some embodiments, R 4 It does not exist, R 2A and R 2B One of them is -OH, and R 3 It is not hydrogen.

[0017] In some embodiments, R 1A and R 1B Each of these can be independent, non-substitutable or placeholder. These are alternative alkyl groups (e.g., haloalkyl, alkoxyalkyl, -CH3, -CH2CH3, -CH(CH3)2, -CF3, or -CH2OCH3).

[0018] In other embodiments, R 1A and R 1B Each of them is independently a substituted alkyl (e.g., a haloalkyl). In some embodiments, R 1A and R 1B is an alkyl group (e.g., unsubstituted or substituted alkyl group (e.g., -CH3)). In some embodiments, R 1A and R 1B It is -CH3.

[0019] In some situations, R 1A It is either -CF3 or -CH2OCH3.

[0020] In other situations, R 1A is hydrogen, R 1B These are alkyl, carbocyrill, heterocyclyl, aryl, or heteroaryl compounds.

[0021] In some embodiments, R 1A and R 1B These atoms, together with the carbon atoms to which they are bonded, form a 3- to 8-membered ring.

[0022] In some aspects, R 1A is a substituted alkyl or unsubstituted C2-C6 alkyl, and R 1B is a substituted or unsubstituted C1-C6 alkyl.

[0023] In some embodiments, each of R 2A and R 2B is independently alkyl (e.g., substituted or unsubstituted alkyl). In some aspects, each of R 2A and R 2B is independently -F.

[0024] In other embodiments, R 2A and R 2B are -CH3, R 3 is alkyl, alkenyl, alkynyl or -OR A where R A is alkyl. In some other embodiments, each of R 2A and R 2B is independently hydrogen, and R 3 is alkyl (e.g., substituted or unsubstituted alkyl).

[0025] In some embodiments, R 3 is alkyl (e.g., substituted or unsubstituted alkyl), alkenyl, alkynyl or -OR A where R A is alkyl. In other embodiments, R 3 is alkyl (e.g., substituted or unsubstituted alkyl).

[0026] In one aspect, a compound according to formula (B):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0027] In some embodiments, n is 1. In other embodiments, n is 2.

[0028] In some embodiments, the compound of formula (B) is of formula (BI): [ka] It is a compound of [the compound].

[0029] In some embodiments, the compound of formula (B) is formula (B-II): [ka] It is a compound of [the compound].

[0030] In some embodiments, the compound of formula (B) is of formula (B-III): [ka] It is a compound of [the compound].

[0031] In some embodiments, the compound of formula (B) is (B-IV), (BV), or (B-VI): [ka] [In the formula, R 2C is hydrogen or alkyl, and R 3 is alkyl, alkenyl, alkynyl or -OR A And here, R A It is a compound of alkyl.

[0032] In some embodiments, the compound of formula (B) is (B-VII), (B-VIII), or (B-IX): [ka] [In the formula, R 3is alkyl, alkenyl, alkynyl or -OR A And here, R A It is an alkyl compound.

[0033] In some embodiments, the compound of formula (B) is of formula (BX): [ka] [In the formula, R 3 is alkyl, alkenyl, alkynyl or -OR A And here, R A It is an alkyl compound.

[0034] In some embodiments, the compound of formula (B) is of formula (B-XII) [ka] [In the formula, R' is alkyl or -OR A And here, R A It is a compound of [where is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, or 3].

[0035] In some embodiments, R 1A and R 1B Each of these is independently an unsubstituted or substituted alkyl (e.g., haloalkyl, alkoxyalkyl, -CH3, -CH2CH3, -CH(CH3)2, -CF3, or -CH2OCH3).

[0036] In other embodiments, R 1A and R 1B Each of them is independently a substituted alkyl (e.g., a haloalkyl). In some embodiments, R 1A and R 1B is an alkyl group (e.g., unsubstituted or substituted alkyl group (e.g., -CH3)). In some embodiments, R 1A and R 1B It is -CH3.

[0037] In some situations, R 1A It is either -CF3 or -CH2OCH3.

[0038] In other situations, R 1A is hydrogen, R 1B These are alkyl, carbocyrill, heterocyclyl, aryl, or heteroaryl compounds.

[0039] In some embodiments, R 1A and R 1B These atoms, together with the carbon atoms to which they are bonded, form a 3- to 8-membered ring.

[0040] In some situations, R 1A is a substituted alkyl or unsubstituted C2-C6 alkyl, and R 1B These are substituted or unsubstituted C1-C6 alkyl groups.

[0041] In some embodiments, R 2A and R 2B Each of them is independently an alkyl (e.g., substituted or unsubstituted alkyl). In some aspects, R 2A and R 2B Each of these is independently -F.

[0042] In other embodiments, R 2A and R 2B is -CH3, R 3 is alkyl, alkenyl, alkynyl or -OR A And here R A is alkyl. In some other embodiments, R 2A and R 2B Each of them is independently a hydrogen atom, and R 3 is an alkyl group (e.g., substituted or unsubstituted alkyl group).

[0043] In some embodiments, R 3This includes alkyl (e.g., substituted or unsubstituted alkyl), alkenyl, alkynyl, or -OR A And here, R A is alkyl. In other embodiments, R 3 is an alkyl group (e.g., substituted or unsubstituted alkyl group).

[0044] In one phase, equation (I): [ka] Compounds or pharmaceutically acceptable salts thereof are provided herein, in which formula (I): R 1A and R 1B Each of them independently is hydrogen, a substituted or unsubstituted alkyl, a carbocykryl, a heterocyclyl, an aryl or heteroaryl, or R 1A and R 1B They form a 3- to 8-membered ring together with the carbon atoms to which they are bonded; R 2A and R 2B Each of these is independently hydrogen, halo, -OR C , alkyl, alkenyl, alkynyl, aryl or heteroaryl, where R C is either hydrogen or alkyl, or R 2A and R 2B They form an oxo group together with the carbon atoms to which they are bonded, and here, R 2A and R 2B Both are not hydrogen at the same time; R 3 This includes hydrogen, alkyl, alkenyl, alkynyl or -OR A And here, R A It is alkyl; R 4 It does not exist, or it is hydrogen; and [ka] represents a single bond or a double bond, where, [ka] If one of them is a double bond, the other [ka] It is a single bond; [ka] If both are single bonds, R 4 is hydrogen; and [ka] If one of them is a double bond, R 4 It does not exist; Here, R 1A , R 3 and R 4 is hydrogen, and R 1B If R is an unsubstituted isopropyl, 2A and R 2B They do not form an oxo group with the carbon atoms to which they are bonded; and R 4 R does not exist, 3 is hydrogen, and R 1A and R 1B If R is -CH3, 2A It is not -CH3, and R 2B It is not -OH.

[0045] In some embodiments, R 1A , R 3 and R 4 is hydrogen, R 1B It is unsubstituted isopropyl, and R 2A and R 2B These do not form oxo groups with the carbon atoms to which they are bonded.

[0046] In some embodiments, R 4 It does not exist, R 3 is hydrogen, R 1A and R 1B is -CH3, R 2AIt is not -CH3, and R 2B It is not -OH.

[0047] In some embodiments, the compound of formula (I) is formula (IA): [ka] It is a compound of [the compound].

[0048] In some embodiments, the compound of formula (I) is of formula (IB): [ka] It is a compound of [the compound].

[0049] In some embodiments, the compound of formula (I) is of formula (IC): [ka] It is a compound of [the compound].

[0050] In some embodiments, the compound of formula (I) is formula (IE), (IF), or (IG): [ka] [ka] [In the formula, R 2C is hydrogen or alkyl, and R 3 is alkyl, alkenyl, alkynyl or -OR A And here, R A It is an alkyl compound.

[0051] In some embodiments, the compound of formula (I) is formula (IH), (II), or (IJ): [ka] [In the formula, R 3is alkyl, alkenyl, alkynyl or -OR A And here, R A It is an alkyl compound.

[0052] In some embodiments, the compound of formula (I) is formula (IK): [ka] [In the formula, R 3 is alkyl, alkenyl, alkynyl or -OR A And here, R A It is an alkyl compound.

[0053] In some embodiments, the compound of formula (I) is of formula (IM) [ka] [In the formula, R' is alkyl or -OR A And here, R A It is a compound of [where is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, or 3].

[0054] In some embodiments, R 1A and R 1B Each of these is independently an unsubstituted or substituted alkyl (e.g., haloalkyl, alkoxyalkyl, -CH3, -CH2CH3, -CH(CH3)2, -CF3, or -CH2OCH3).

[0055] In some embodiments, R 1A and R 1B Each of these is independently a substituted alkyl group (e.g., a haloalkyl group).

[0056] In some embodiments, R 1A It is either -CF3 or -CH2OCH3.

[0057] In some embodiments, R1A and R 1B is an alkyl group (e.g., unsubstituted or substituted alkyl group (e.g., -CH3)).

[0058] In some embodiments, R 1A and R 1B It is -CH3.

[0059] In some embodiments, R 1A and R 1B These atoms, together with the carbon atoms to which they are bonded, form a 3- to 8-membered ring.

[0060] In some embodiments, R 1A is hydrogen, R 1B These are alkyl, carbocyrill, heterocyclyl, aryl, or heteroaryl compounds.

[0061] In some embodiments, R 1A R is a substituted alkyl or an unsubstituted C2-C6 alkyl, 1B These are substituted or unsubstituted C1-C6 alkyl groups.

[0062] In some embodiments, R 2A and R 2B Each of them is independently an alkyl group (e.g., substituted or unsubstituted alkyl group).

[0063] In some embodiments, R 2A and R 2B Each of these is independently -F.

[0064] In some embodiments, R 2A and R 2B is -CH3, R 3 is alkyl, alkenyl, alkynyl, or -OR A And here R A It is alkyl.

[0065] In some embodiments, R 2A and R2B is -F.

[0066] In some embodiments, R 3 This includes alkyl (e.g., substituted or unsubstituted alkyl), alkenyl, alkynyl, or -OR A And here R A It is alkyl.

[0067] In some embodiments, R 3 is an alkyl group (e.g., substituted or unsubstituted alkyl group).

[0068] In some embodiments, R 2A and R 2B Each of them is independently hydrogen, and R 3 is an alkyl group (e.g., substituted or unsubstituted alkyl group).

[0069] In one phase, equation (II): [ka] Compounds or pharmaceutically acceptable salts thereof are provided herein, in formula (II): R 1A and R 1B Each of them independently is hydrogen, a substituted or unsubstituted alkyl, a carbocykryl, a heterocyclyl, an aryl or heteroaryl, or R 1A and R 1B They form a 3- to 8-membered ring together with the carbon atoms to which they are bonded; R 2A and R 2B Each of these is independently hydrogen, halo, -OR C , alkyl, alkenyl, alkynyl, aryl or heteroaryl, where R C is either hydrogen or alkyl, or R 2A and R 2B They form an oxo group together with the carbon atoms to which they are bonded, and here, R 2A and R 2BBoth are not hydrogen at the same time; R 3 This includes hydrogen, alkyl, alkenyl, alkynyl or -OR A And here, R A It is alkyl; R 4 It does not exist, or it is hydrogen; and [ka] represents a single bond or a double bond, where, [ka] If one of them is a double bond, the other [ka] It is a single bond; [ka] If both are single bonds, R 4 is hydrogen; and [ka] If one of them is a double bond, R 4 It does not exist; However, R 4 R does not exist, 2A is -OH, and R 2B is hydrogen or -CF3, and R 1A and R 1B If R is -CH3, 3 It is not hydrogen; and R 1A and R 1B is -CH3, and R 3 If R is hydrogen, 2A and R 2B These do not form oxo groups with the carbon atoms to which they are bonded.

[0070] In some embodiments, R 4 It does not exist, R 2Aand R 2B One of them is -OH, and R 3 It is not hydrogen.

[0071] In some embodiments, the compound of formula (II) is formula (II-A): [ka] It is a compound of [the compound].

[0072] In some embodiments, the compound of formula (II) is formula (II-B): [ka] It is a compound of [the compound].

[0073] In some embodiments, the compound of formula (II) is formula (II-C): [ka] It is a compound of [the compound].

[0074] In some embodiments, the compound of formula (II) is formula (II-D): [ka] It is a compound of [the compound].

[0075] In some embodiments, the compound of formula (II) is (II-E), (II-F), or (II-G): [ka] [ka] [In the formula, R 2C is hydrogen or alkyl (e.g., substituted or unsubstituted alkyl), and R 3 [The compound is alkyl (e.g., substituted or unsubstituted alkyl)] ru.

[0076] In some embodiments, the compound of formula (II) is (II-H), (II-I), or (II-J): [ka] [In the formula, R 3 is alkyl, alkenyl, alkynyl or -OR A And here, R A It is an alkyl compound.

[0077] In some embodiments, the compound of formula (II) is (II-K) [ka] [In the formula, R' is alkyl or -OR A And here, R A It is a compound of [where is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, or 3].

[0078] In some embodiments, R 1A and R 1B Each of these is independently an unsubstituted or substituted alkyl (e.g., haloalkyl, alkoxyalkyl, -CH3, -CH2CH3, -CH(CH3)2, -CF3, or -CH2OCH3).

[0079] In some embodiments, R 1A and R 1B Each of these is independently a substituted alkyl group (e.g., a haloalkyl group).

[0080] In some embodiments, R 1A It is either -CF3 or -CH2OCH3.

[0081] In some embodiments, R 1A and R 1B is an alkyl group (e.g., unsubstituted or substituted alkyl group (e.g., -CH3)).

[0082] In some embodiments, R 1A and R 1B It is -CH3.

[0083] In some embodiments, R 1A and R 1B These atoms form a ring together with the carbon atoms to which they are bonded.

[0084] In some embodiments, R 1A is hydrogen, R 1B These are alkyl, carbocyrill, heterocyclyl, aryl, or heteroaryl compounds.

[0085] In some embodiments, R 2A and R 2B Each of them is independently an alkyl group (e.g., substituted or unsubstituted alkyl group).

[0086] In some embodiments, R 3 is an alkyl group (e.g., substituted or unsubstituted alkyl group).

[0087] In some embodiments, R 2A and R 2B Each of them is independently hydrogen, and R 3 is an alkyl group (e.g., substituted or unsubstituted alkyl group).

[0088] In some embodiments, R 2A and R 2B Each of these is independently -F.

[0089] In some embodiments, R 2A and R 2B is -CH3, R 3 is alkyl, alkenyl, alkynyl, or -OR A And here R A It is alkyl.

[0090] In some embodiments, R 2Aand R 2B is -F.

[0091] In some embodiments, R 1A R is a substituted alkyl or an unsubstituted C2-C6 alkyl, 1B These are substituted or unsubstituted C1-C6 alkyl groups.

[0092] In some aspects, the compound is given by formula (III): [ka] [In the formula, R 1A and R 1B Each of them is a substituted or unsubstituted alkyl group; R 2A and R 2B Each of them independently contains hydrogen, -OR C or alkyl, where R C is either hydrogen or alkyl, or R 2A and R 2B They form an oxo group together with the carbon atoms to which they are bonded, and here, R 2A and R 2B Both are not hydrogen at the same time; R 3 It is alkyl; R 4 It does not exist, or it is hydrogen; and [ka] represents a single bond or a double bond, where, [ka] If one of them is a double bond, the other [ka] It is a single bond; [ka] If both are single bonds, R4 is hydrogen; and [ka] If one of them is a double bond, R 4 It is a compound of [that which does not exist] or a pharmaceutically acceptable salt thereof.

[0093] In some embodiments, R 1A and R 1B Each of these is -CH3.

[0094] In some embodiments, R 2A and R 2B These atoms form an oxo group together with the carbon atoms to which they are bonded.

[0095] In some embodiments, R 3 It is -CH2CH3.

[0096] In some embodiments, R 2A is -OH, and R 2B H is H.

[0097] In some embodiments, R 2A is -CH3, R 2B H is H.

[0098] In some embodiments, R 2A is -OH, and R 2B It is -CH3.

[0099] In some embodiments, R 1A It is -CF3.

[0100] In certain contexts, pharmaceutical compositions comprising compounds described herein or pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers are provided herein.

[0101] In a certain context, a method for inducing sedation or anesthesia is provided herein, which comprises administering an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition thereof to a subject.

[0102] In a given context, a method for treating or preventing a disorder described herein is provided herein, the method comprising administering an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition thereof to a subject in need of such treatment or prevention.

[0103] In some embodiments, the disorder is an autoimmune disorder.

[0104] In some embodiments, the disorders are rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and psoriasis vulgaris.

[0105] In some embodiments, the disorder is a metabolic disorder.

[0106] 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 GI, anal disorders (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas), colon polyps, cancer, or colitis.

[0107] In some embodiments, the disorder is inflammatory bowel disease.

[0108] In some embodiments, the disorder is cancer, diabetes, or sterol synthesis disorder.

[0109] In one aspect, a method for treating or preventing a CNS-related condition is provided herein, comprising the step of administering an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition thereof to a subject in need of such treatment or prevention. In some embodiments, CNS-related conditions include adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, and social phobia), cognitive disorders (including Alzheimer's disease and other forms of dementia (e.g., frontotemporal dementia)), dissociative disorders, eating disorders, mood disorders (including depression (e.g., postpartum depression)), bipolar disorder, dysthymic disorder, and suicidal tendencies), schizophrenia or other psychotic disorders (including schizoaffective psychosis), sleep disorders (including insomnia), substance-related disorders, personality disorders (including obsessive-compulsive personality disorder), and autism spectrum disorders (Shank group proteins). These include mutations (e.g., those involving Shank3), neurodevelopmental disorders (such as Rett syndrome and tuberous sclerosis complex), multiple sclerosis, sterol synthesis disorders, pain (acute and chronic pain; headaches, e.g., migraines), secondary brain damage to a medical condition (such as hepatic encephalopathy and anti-NMDA receptor encephalitis), paroxysmal disorders (such as status epilepticus and monogenic epilepsy, e.g., Dravet disease), stroke, traumatic brain injury, motor impairments (such as Huntington's disease and Parkinson's disease), visual impairment, hearing impairment, or tinnitus.

[0110] In some embodiments, the disorder is Huntington's disease. In some embodiments, the disorder is Parkinson's disease. In some embodiments, the disorder is an inflammatory disease (e.g., lupus).

[0111] In some embodiments, the impairment is sterol synthesis impairment.

[0112] In some embodiments, the disorder is Smith-Lemle-Oppitz syndrome (SLOS). In some embodiments, the disorder is desmosterolosis. In some embodiments, the disorder is sitosterolemia. In some embodiments, the disorder is cerebral tenosynovitis xanthomatosis (CTX). In some embodiments, the disorder is mevalonate kinase deficiency (MKD). In some embodiments, the disorder is SC4MOL gene mutation (SMO deficiency). In some embodiments, the disorder is Niemann-Pick disease. In some embodiments, the disorder is autism spectrum disorder (ASD). In some embodiments, the disorder is associated with phenylketonuria.

[0113] Other purposes and advantages will become apparent to those skilled in the art by considering the following detailed description, examples, and claims. definition chemical definition

[0114] The definitions of specific functional groups and chemical terms are explained in detail below. Chemical elements are identified according to the periodic table (CAS version, Handbook of Chemistry and Physics, 75th edition, inside cover), and specific functional groups are usually defined as they appear therein. Furthermore, general rules of organic chemistry, as well as specific functional parts and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods This is described in ds of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0115] Isomers can be isolated from the mixture by methods known to those skilled in the art (including chiral high-pressure liquid chromatography (HPLC), and the formation and crystallization of chiral salts); or preferred isomers can be prepared by asymmetric synthesis. For example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents See and Optical Resolutions p.268 (edited by ELEliel, 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.

[0116] The "enantiomer excess" ("ee") or "% enantiomer excess" ("%ee") of a composition means that one enantiomer is present in excess of the other enantiomer in the composition. For example, a composition may contain 90% of one enantiomer, e.g., the S enantiomer, and 10% of the other enantiomer, i.e., the R enantiomer.

[0117] ee = (90 - 10) / 100 = 80%.

[0118] Therefore, a composition containing 90% of one enantiomer and 10% of the other enantiomer is said to have an enantiomer excess of 80%.

[0119] The “diastereomer excess” ("de") or “% diastereomer excess” ("%de") of a composition means that a particular diastereomer is present in excess of one or more other diastereomers in the composition. For example, a composition may contain 90% of one diastereomer and 10% of one or more other diastereomers.

[0120] de = (90 - 10) / 100 = 80%.

[0121] Therefore, a composition containing 90% of one diastereomer and 10% of one or more different diastereomers is said to have an 80% diastereomer excess.

[0122] When a range of values ​​is enumerated, it is intended to include each value and subrange within that range. For example, "C 1~6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 , and C 5~6 It is intended to include alkyl groups.

[0123] The following terms are intended to have the meanings set forth below and are useful in understanding the scope intended of this specification and the present invention. When describing the present invention (which may encompass compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions), the following terms, where otherwise indicated, are used. Unless otherwise specified, the following meanings apply. It should also be understood that, where used herein, any of the parts defined below may be substituted with various substituents, and that each definition is intended to encompass the substituted parts within those ranges as set forth below. Unless otherwise specified, the term “substituted” is defined as set forth below. It should further be understood that, where used herein, the terms “group” and “radical” may be considered interchangeable. The articles “a” and “an” may be used herein to indicate that the grammatical object of the article is one or more (i.e., at least one). For example, “an analogue” means one analog or more analogs.

[0124] "Aliphatic" means an alkyl group, alkenyl group, alkynyl group, or cycloalkyl group as defined herein.

[0125] "Alkyl" refers to a radical of a linear or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C"). 1~20 "Alkyl" refers to a group having 1 to 12 carbon atoms. In some embodiments, an alkyl group has 1 to 12 carbon atoms. 1~12 ("alkyl"). In some embodiments, the alkyl group has 1 to 10 carbon atoms ("C"). 1~10 Alkyl). In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C"). 1~9 Alkyl). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C"). 1~8Alkyl). In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C"). 1~7 Alkyl). In some embodiments, the alkyl group has 1 to 6 carbon atoms (also referred to herein as "lower alkyl"). 1~6 Alkyl). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C"). 1~5 Alkyl). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C"). 1~4 (alkyl). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C"). 1~3 Alkyl). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C"). 1~2 Alkyl). In some embodiments, the alkyl group has one carbon atom ("C1 alkyl"). In some embodiments, the alkyl group has two to six carbon atoms ("C1 alkyl"). 2~6 Alkyl). C 1~6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and others. Unless otherwise specified, each alkyl group may be independently substituted as needed, i.e., unsubstituted ("unsubstituted alkyl") or with one or more substituents; for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, the alkyl group is unsubstituted C 1~10 It is an alkyl group (e.g., -CH3). In certain embodiments, the alkyl group is a substituted C 1~10It is an alkyl group. Common abbreviations for alkyl groups include Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2).

[0126] "Alkylene" refers to an alkyl group in which two hydrogen atoms are removed to give a divalent radical, and which may or may not be substituted. Examples of unsubstituted alkylene groups include methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), and pentylene (-CH2CH2 Examples of substituted alkylene groups (e.g., substituted with one or more alkyl(methyl) groups) include, but are not limited to, 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 Examples include, but are not limited to, (CH3)2CH2CH2-, -CH2C(CH3)2CH2-, and -CH2CH2C(CH3)2-). When a range or number of carbon atoms is provided for a particular alkylene group, this range or number is understood to mean a range or number of carbon atoms in the divalent chain of straight carbon atoms. The alkylene group may be substituted with or unsubstituted with one or more substituents as described herein.

[0127] "Alkenyl" refers to a radical of a linear or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., one, two, three, or four carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., one, two, three, or four carbon-carbon triple bonds). 2~20 An alkenyl is a group that has 2 to 10 carbon atoms. In certain embodiments, the alkenyl group does not contain any triple bonds. In some embodiments, the alkenyl group has 2 to 10 carbon atoms. 2~10 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C"). 2~9 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C"). 2~8 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C"). 2~7 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C"). 2~6 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C"). 2~5 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C"). 2~4 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C"). 2~3 "Alkenyl"). In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). One or more carbon-carbon double bonds may be located internally (e.g., 2-butenyl) or at the terminal (e.g., 1-butenyl). C 2~4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), and butadienyl (C4). 2~6 An example of an alkenyl group is the aforementioned C 2~4Examples of alkenyl groups include pentenyl (C5), pentadienyl (C5), and hexenyl (C6). Further examples of alkenyls include heptenyl (C7), octenyl (C8), and octatrienyl (C8). Unless otherwise specified, each presence of an alkenyl group can be independently substituted as needed, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, the alkenyl group is an unsubstituted C 2~10 It is an alkenyl. In certain embodiments, the alkenyl group is a substituted C 2~10 It is Alkenil.

[0128] "Alkynnyl" refers to a radical of a linear or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., one, two, three, or four carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., one, two, three, or four carbon-carbon double bonds). 2~20 This refers to an "alkynyl" group. In certain embodiments, the alkynyl group contains no double bonds at all. In some embodiments, the alkynyl group has 2 to 10 carbon atoms ("C"). 2~10 Alkinyl) In some embodiments, alkinyl The group has 2 to 9 carbon atoms ("C 2~9 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C"). 2~8 In some embodiments, the alkynyl group has 2 to 7 carbon atoms ("C"). 2~7 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C"). 2~6 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C"). 2~5 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C").2~4 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C"). 2~3 "Alkynyl"). In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). One or more carbon-carbon triple bonds may be located internally (e.g., 2-butynyl) or at the terminal (e.g., 1-butynyl). C 2~4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), and 2-butynyl (C4). 2~6 An example of an alkenyl group is the aforementioned C 2~4 Examples include alkynyl groups, as well as pentynyl (C5), hexynyl (C6), and the like. Further examples of alkynyls include heptynyl (C7), octinyl (C8), and the like. Unless otherwise specified, each presence of an alkynyl group can be independently substituted as needed, i.e., unsubstituted ("unsubstituted alkynyl") or with one or more substituents; for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkynyl"). In certain embodiments, the alkynyl group is an unsubstituted C 2~10 It is an alkynyl group. In certain embodiments, the alkynyl group is a substituted C 2~10 It is alkinyl.

[0129] The term “heteroalkyl” means, as used herein, an alkyl group as defined herein, which further contains one or more (e.g., one, two, three, or four) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) in its parent chain, wherein the one or more heteroatoms are inserted between adjacent carbon atoms in its parent carbon chain, and / or the one or more heteroatoms are inserted between a carbon atom and its parent molecule (i.e., between bonding sites). In certain embodiments, a heteroalkyl group is a saturated group having one to ten carbon atoms and one, two, three, or four heteroatoms ("hetero-C"). 1~10"Alkyl" refers to a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms ("hetero C 1~9 A heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms ("hetero C"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms ("hetero C"). 1~8 A heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms ("hetero C"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms ("hetero C"). 1~7 A heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ("hetero C"). In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ("hetero C"). 1~6 A heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("hetero C 1~5 A heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms ("hetero C"). In some embodiments, the heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms ("hetero C"). 1~4 A heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (("hetero C 1~3 A heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (("hetero C 1~2 In some embodiments, a heteroalkyl group is a saturated group having one carbon atom and one heteroatom ("heteroC1 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having two to six carbon atoms and one or two heteroatoms ("heteroC1 alkyl"). 2~6 It is an alkyl group. Unless otherwise specified, each example of a heteroalkyl group is independently substituted. Either it is not substituted ("unsubstituted heteroalkyl") or it is substituted with one or more substituents ("substituted heteroalkyl"). In certain embodiments, the heteroalkyl is an unsubstituted heteroC 1~10 It is alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC 1~10 It is alkyl.

[0130] "Aryl" refers to a radical ("C") of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system in which 6 to 14 ring carbon atoms and 0 heteroatoms are provided to the aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement). 6~14 This refers to an aryl group. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10 "Aryl"; for example, naphthyl (such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C"). 14"Aryl" (e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused with one or more carbocyrillic or heterocyclyl groups, where the bonding radical or bond site is located on the aryl ring, and in such cases the number of carbon atoms still indicates the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, those derived from acetantrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluorantene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indan, indene, naphthalene, octacene, octafen, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiaden, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. In particular, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each presence of an aryl group is independently substituted as needed, i.e., either unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In a particular embodiment, the aryl group is an unsubstituted C 6~14 It is aryl. In certain embodiments, the aryl group is substituted C 6~14 It is Ariel.

[0131] 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.

[0132] Typical examples of substitution aryls include the following: [ka] Here, R 56 and R 57 One of them can be hydrogen, and R 56 and R 57At least one of these is independently a C1-C8 alkyl, C1-C8 haloalkyl, 4-10 member heterocyclyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 , NR 58 SOR 59 , NR 58 SO2R 59 COOalkyl, COOaryl, CONR 58 R 59 CONR 58 Ure 59 , NR 58 R 59 SO2NR 58 R 59 Selected from S-alkyl, SOalkyl, SO2alkyl, S-aryl, SOaryl, SO2aryl; or R 56 and R 57 These can be linked together to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms (including, as necessary, one or more heteroatoms selected from the group N, O, or S). 60 and R 61 These are independently hydrogen, C1-C8 alkyl, and C1-C 4-haloalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, substitution C6-C 10 These are aryl, 5-10 member heteroaryl, or substituted 5-10 member heteroaryl.

[0133] A "condensed aryl" is an aryl ring in which two of its ring carbons are shared with a second aryl ring or heteroaryl ring, or with a carbocykyl ring or heterocycline ring.

[0134] A "heteroaryl" is 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 the cyclic arrangement) in which a ring carbon atom and 1-4 ring heteroatoms are provided to the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the bond site can be a carbon or nitrogen atom, wherever the bond valency allows. A heteroaryl bicyclic ring system may contain one or more heteroatoms in one or both rings. A "heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused with one or more carbocykyl or heterocyclyl groups, where the bond site is located on the heteroaryl ring, and in such cases the number of ring members still refers to the number of ring members in the heteroaryl ring system. "Hyperaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more aryl groups, where the bond site is located on the aryl ring or the heteroaryl ring, and in such cases, the number of ring members indicates the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups where one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the bond site may be located on either ring, i.e., on the ring with a heteroatom (e.g., 2-indolyl) or on the ring without a heteroatom (e.g., 5-indolyl).

[0135] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system in which a ring carbon atom and 1-4 ring heteroatoms are provided to the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system in which a ring carbon atom and 1-4 ring heteroatoms are provided to the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system in which a ring carbon atom and 1-4 ring heteroatoms are provided to the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has one or two ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each presence of a heteroaryl group is independently substituted as necessary, i.e., either unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0136] Examples of five-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Examples of five-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. 3 Examples of five-membered heteroaryl groups containing one heteroatom include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Examples of five-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Examples of six-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Examples of six-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Examples of six-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetradinyl, respectively. Examples of seven-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Examples of 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranil, benzoisofuranil, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolidinyl, and prinyl. Examples of 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthylidinyl, pteridinyl, quinolinil, isoquinolinil, sinnolinil, quinoxalinil, phthalazinyl, and quinazolinil.

[0137] Typical examples of heteroaryls include: [ka] These are listed, where each Z is carbonyl, N, NR 65 Selected from O and S; R 65 These are independently hydrogen, C1-C8 alkyl, and C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 They are aryl and 5- to 10-membered heteroaryls.

[0138] A "carbocyclyl" or "carbocyclic" structure is a non-aromatic ring system with 3 to 10 ring carbon atoms ("C"). 3~10 A carbocyclyl group is a radical of a non-aromatic cyclic hydrocarbon group having 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 Examples of carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). 3~8 As for the carbocyclyl group, the above C 3~6 Carbocyclyl group, and cycloheptyl (C7), cy Examples include, but are not limited to, chloroheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienylenyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), and bicyclo[2.2.2]octanyl (C8). 3~10 As for the carbocyclyl group, the above C 3~8 Carbocyclyl group, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C9) 10 ), spiro[4.5]decanil(C 10Examples include, but are not limited to, the above. When the above examples are illustrated, in certain embodiments the carbocyclyl group may be monocyclic ("monocyclic carbocyclyl") or include fused, bridging, or spirocyclic systems (e.g., bicyclic systems ("bicyclic carbocyclyl")) and may be saturated or partially unsaturated. "Carbocyclyl" also includes cyclic systems in which a carbocyclyl ring as defined above is fused with one or more aryl or heteroaryl groups, where the bond site is on the carbocyclyl ring, and in such cases the number of carbons still refers to the number of carbons in the carbocyclic system. Unless otherwise specified, each presence of a carbocyclyl group may be independently substituted as needed, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments the carbocyclyl group may be unsubstituted C 3~10 It is a carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C 3~10 It is carbocyclyl.

[0139] In some embodiments, "carbocyrill" is a monocyclic saturated carbocyrill group having 3 to 10 ring carbon atoms ("C 3~10 It is a cycloalkyl group. 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 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3~6 Examples of cycloalkyl groups include the above C 5~6Examples include cycloalkyl groups, as well as cyclopropyl (C3) and cyclobutyl (C4). 3~8 Examples of cycloalkyl groups include the above C 3~6 Examples include cycloalkyl groups, as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each cycloalkyl group is independently either unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, the cycloalkyl group is unsubstituted C 3~10 It is a cycloalkyl group. In certain embodiments, the cycloalkyl group is a substituted C 3~10 It is a cycloalkyl group.

[0140] A "heterocyclyl" or "heterocyclic" is a radical of a 3- to 10-membered non-aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In a heterocyclyl group containing one or more nitrogen atoms, the bond site can be a carbon or nitrogen atom, if the valency allows. A heterocyclyl group can be a monocyclic ring system ("monocyclic heterocyclyl"), a fused ring system, a bridging ring system, or a spiro-ring system (e.g., a bicyclic ring system ("bicyclic heterocyclyl")), and can be saturated or partially unsaturated. A heterocyclyl bicyclic ring system may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes a ring system in which a heterocyclyl ring as defined above is fused with one or more carbocyclyl groups, where the bond site is located on the carbocyclyl or heterocyclyl ring, or on a ring system in which a heterocyclyl ring as defined above is fused with one or more aryl or heteroaryl groups, where the bond site is located on the heterocyclyl ring. The heterocyclyl group is located on a rosykrill ring, and in such cases, the number of ring members still indicates the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each heterocyclyl presence is independently substituted as necessary, i.e., either unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0141] In some embodiments, the heterocyclyl group is a 5- to 10-membered non-aromatic ring system having a ring carbon atom 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 a ring carbon atom 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 a ring carbon atom 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 heterocyclil has one or two ring heteroatoms selected from nitrogen, oxygen, and sulfur.

[0142] Examples of three-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxyranil, and thiorenyl. Examples of four-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanil, and thietanil. Examples of five-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranil, dihydrofuranil, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Examples of five-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanil, oxasulfuranil, disulfuranil, and oxazolidine-2-one. Examples of five-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Examples of six-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranil, dihydropyridinyl, and thianil. Examples of six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinil, dithianil, and dioxanil. Examples of six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanil. Examples of seven-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanil, oxepanil, and thiepanil. Examples of eight-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azokanil, oxekanil, and thiokanil. Examples of five-membered heterocyclyl groups condensed to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic rings) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranil, dihydrobenzothienyl, and benzoxazolinonil.Examples of six-membered heterocyclyl groups condensed to an aryl ring (also referred to herein as 6,6-bicyclic heterocyclic rings) include, but are not limited to, tetrahydroquinolinyl and tetrahydroisoquinolinyl.

[0143] A "nitrogen-containing heterocyclyl" group refers to 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.

[0144] When "hetero" is used to describe a compound or a group present on a compound, it means that one or more carbon atoms in the compound or group are replaced by nitrogen, oxygen, or sulfur heteroatoms. Hetero may be applied to any of the hydrocarbyl groups described above (e.g., alkyl, e.g., heteroalkyl; cycloalkyl, e.g., heterocyclyl; aryl, e.g., heteroaryl; cycloalkenyl, e.g., cycloheteralkenyl, etc.) having one to five, and in particular, one to three heteroatoms.

[0145] "Ashil" is -C(O)R 20 This refers to a radical, and here, R 20 This includes hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl, as defined herein. "Alkanoyl" is R 20The group other than hydrogen is the acyl group. Representative acyl groups include formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), --C(O)-C1-C8 alkyl, and -C(O)-(CH2). t (C6-C 10 aryl), -C(O)-(CH2) t (5-10 member heteroaryl), -C(O)-(CH2) t (C3-C 10 Cycloalkyl) and -C(O)-(CH2) t Examples include, but are not limited to, (4- to 10-membered heterocyclines) (where t is an integer from 0 to 4). In a particular embodiment, R 21 C1-C8 alkyl groups substituted with halo or hydroxyl; or C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 These are aryl, arylalkyl, 5-10 membered heteroaryl, or heteroarylalkyl (each of which is substituted with an unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy).

[0146] "alkoxy" means -OR 29 It refers to the base, and here, R 29 These are substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted carbocyclyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heteroaryl groups. Certain alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Certain alkoxy groups are lower alkoxy groups, i.e., having 1 to 6 carbon atoms. Further specific alkoxy groups have 1 to 4 carbon atoms.

[0147] In a particular embodiment, R 29 is amino, substituted amino, C6-C 10 Aryl, aryloxy, carboxyl, cyano, C3-C 10 One or more substituents selected from the group consisting of cycloalkyl, 4-10 member heterocyclyl, halogen, 5-10 member 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 1 It is a substituted group. An example of a "substituted alkoxy" group is -O-(CH2) t (C6-C 10 aryl), -O-(CH2) t (5-10 member heteroaryl), -O-(CH2) t (C3-C 10 Cycloalkyl) and -O-(CH2) t Examples include, but are not limited to, 4- to 10-membered heterocyclyl groups, where t is an integer from 0 to 4, and any existing aryl, heteroaryl, cycloalkyl, or heterocyclyl group may itself be substituted with an unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. Particularly exemplary "substituted alkoxy" groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2.

[0148] "Amino" refers to the -NH2 radical.

[0149] An "oxo group" refers to -C(=O)-.

[0150] "Substituting amino acid" refers to the compound of the formula -N(R 38 ) refers to the amino group of 2, where R 38R is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or an amino protecting group, where R 38 At least one of them is not hydrogen. In a particular embodiment, each R 38 These are independently hydrogen, C1-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, and C6-C 10 Aryl, 5-10 member heteroaryl, 4-10 member heterocyclyl, or C3-C 10 Cycloalkyl; or C1-C8 alkyl substituted with halo or hydroxyl; C3-C8 alkenyl substituted with halo or hydroxyl; C3-C8 alkynyl substituted with halo or hydroxyl, or -(CH2) t (C6-C 10 Aryl), -(CH2) t (5-10 member heteroaryl), -(CH2) t (C3-C 10 Cycloalkyl) or -(CH2) t Selected from (4-10 member heterocyclyls), where t is an integer from 0 to 8, each of which is substituted with an unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxyl; or both R 38 The groups link together to form an alkylene group.

[0151] Examples of "substituted amino" groups include -NR 39 -C1-C8 alkyl, -NR 39 -(CH2) t (C6-C 10 Ariel), -NR 39 -(CH2) t (5-10 member heteroaryl), -NR 39 -(CH2) t (C3-C 10 Cycloalkyl) and -NR 39-(CH2) t Examples include (4-10 member heterocyclyls), but are not limited to these, where t is an integer from 0 to 4, for example, 1 or 2, and each R 39 The group independently represents H or C1-C8 alkyl; any alkyl group present may be substituted by a halo, substituted or unsubstituted amino or hydroxyl group; any aryl, heteroaryl, cycloalkyl or heterocyclyl group present may be substituted by an unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxyl group. To avoid misunderstanding, the term “substituted amino” includes alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino and substituted dialkylamino groups, as defined below. Substituted aminos include both monosubstituted and disubstituted amino groups.

[0152] "Carboxylate" refers to the -C(O)OH radical.

[0153] "Cyano" refers to the -CN radical.

[0154] "Halo" or "halogen" refers to fluoro(F), chloro(Cl), bromo(Br), and iodine(I). In certain embodiments, the halo group is fluoro or chloro.

[0155] A "haloalkyl" is an alkyl radical in which one or more halogens are substituted for an alkyl group. Typical haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, and tetrafluoroethyl.

[0156] "Hydroxy" refers to the -OH radical.

[0157] "Nitro" refers to the -NO2 radical.

[0158] "Thioketo" refers to the S group.

[0159] Alkyl, alkenyl, alkynyl, carbocyrill, heterocyclyl, aryl, and heteroaryl groups as defined herein may be substituted as necessary (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyrill, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl groups). In general, the term "substituted" means, whether or not preceded by the term "as necessary," that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that, when substituted, produces a stable compound, e.g., a compound that does not undergo spontaneous transformation (e.g., rearrangement, cyclization, elimination, or other reactions). Unless otherwise indicated, a “substituted” group has substituents at one or more substituted positions of that group, and when two or more positions in any given structure are substituted, the substituents are either the same or different at each position. The term “substituted” is intended to include all acceptable substituents of an organic compound, substitution by any substituents described herein that form a stable compound. The present invention assumes all such combinations for the purpose of obtaining a stable compound. For the purposes of the present invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any preferred substituents, as described herein, that satisfy the bond valence of the heteroatom and consequently form a stable moiety.

[0160] Examples of carbon atom substituents include halogens, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, and -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3+ X - 、-N(OR cc )R bb 、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-S C(=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 Haloalkyl, C 2~10 Alkenil, C 2~10 Alkinyl, C 3~10 Carbocyclyl, 3-14 member heterocyclyl, C 6~14 Examples include, but are not limited to, aryls and 5- to 14-membered heteroaryls. Here, each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted by a group; or two geminal hydrogens on a carbon atom =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 bbOr = NOR cc Replaced by the base;

[0161] R aa Each of these beings is independent of C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenil, C 2~10 Alkinyl, C 3~10 Carbocyclyl, 3-14 member heterocyclyl, C 6~14 Selected from aryls and 5-14 member heteroaryls, or two R aa The groups are linked to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the base;

[0162] R bb Each of these entities exists independently as hydrogen, -OH, and -OR. aa , -N(R cc )2, -CN, -C(=O)R aa -C(=O)N(R cc )2, -CO2R aa , -SO2R aa -C(=NR cc )OR aa -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc -SOR aa -C(=S)N(R cc )2, -C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenil, C 2~10Alkinyl, C 3~10 Carbocyclyl, 3-14 member heterocyclyl, C 6~14 Selected from aryls and 5-14 member heteroaryls, or two R bb The groups are linked to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the base;

[0163] R cc Each of these entities independently contains hydrogen and C. 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenil, C 2~10 Alkinyl, C 3~10 Carbocyclyl, 3-14 member heterocyclyl, C 6~14 Selected from aryls and 5-14 member heteroaryls, or two R cc The groups are linked to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the base;

[0164] R dd Each of these entities is independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff -SH, -SR ee -SSR ee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee , -OCO2R ee-C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R e e , -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 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10Selected from aryls and 5-10 membered heteroaryls, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. gg Substituted by or two geminal R dd Substituents can link together to form either =O or =S;

[0165] R ee Each of these beings is independent of C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~10 Carbocyclyl, C 6~10 Selected from aryls, 3-10 membered heterocyclyls, and 3-10 membered heteroaryls, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. gg Substituted with the base;

[0166] R ff Each of these entities independently contains hydrogen and C. 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 Selected from aryls and 5-10 member heteroaryls, or two R ff The groups are linked to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. gg Substituted with the base;

[0167] R gg Each of these entities is independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6Alkyl, -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 1~6Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1~6 Alkyl), -SO2N(C 1~6 Alkyl)2,-SO2NH(C 1~6 Alkyl), -SO2NH2, -SO2C 1~6 Alkyl, -SO2OC 1~6 Alkyl, -OSO2C 1~6 Alkyl, -SOC 1~6 Alkyl, -Si(C 1~6 Alkyl)3,-OSi(C 1~6 Alkyl )3-C(=S)N(C 1~6 Alkyl)2, C(=S)NH(C 1~6 Alkyl), C(=S)NH2, -C(=O)S(C 1~6 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 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~10 Carbocyclyl, C 6~10 It is either an aryl, a 3-10 member heterocyclyl, a 5-10 member heteroaryl; or two geminal Rs. gg Substituents can link together to form =O or =S; where X - It is a counterion.

[0168] A "counterion" or "anionic counterion" is a negatively charged group that associates with a cationic quaternary amino group to maintain electrical neutrality. Examples of counterions include halide ions (e.g., F - Cl - , Br - , I - ), NO3 - ClO4 - , OH -H2PO4 - HSO4 - SO4 -2 Examples include sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.) and carboxylate ions (e.g., acetate, ethanolate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0169] Nitrogen atoms can be substituted or unsubstituted, wherever the bond valency allows, and may include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, and -OR. aa , -N(R cc )2, -CN, -C(=O)R aa -C(=O)N(R cc )2, -CO2R aa , -SO2R aa -C(=NR bb )R aa -C(=NR cc )OR aa -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc -SOR aa -C(=S)N(R cc )2, -C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenil, C 2~10 Alkinyl, C 3~10 Carbocyclyl, 3-14 member heterocyclyl, C6~14 Examples include, but are not limited to, aryl and 5- to 14-membered heteroaryls, or two R atoms bonded to a nitrogen atom. cc The groups link together to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with R aa , R bb , R cc and R dd This is as defined above.

[0170] 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 in any way by the exemplary enumeration of substituents described above. Other definitions

[0171] The term "pharmaceutically acceptable salt" refers to a salt that, within reasonable medical standards, is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, or allergic reactions, and that is balanced by a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the field. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66, 1-19. Examples of pharmaceutically acceptable salts of the compounds of the present invention include salts derived from appropriate inorganic acids, inorganic bases, organic acids, and organic bases. Examples of acceptable, non-toxic acid addition salts are salts of amino groups formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by other methods used in the field, such as ion exchange. Other pharmaceutically acceptable salts include adipines, alginates, ascorbic acid, aspartates, benzenesulfons, benzoates, bisulfates, borates, butyrates, camphorates, camphor sulfons, citrates, cyclopentanepropionates, diglucons, dodecyl sulfates, ethanesulfons, formates, fumarates, glucoheptons, glycerophosphates, glucons, hemisulfates, heptanoates, hexanoates, hydroiodides, and 2-hydroxyethanesulfons. Examples include 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 Examples include alkyl)4 salts. Typical alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further pharmaceutically acceptable salts, where appropriate, include non-toxic ammonium, quaternary ammonium, and amine cations formed with counterions such as halide ions, hydroxide ions, carbonate ions, sulfate ions, phosphate ions, nitrate ions, lower alkyl sulfonate ions, and aryl sulfonate ions.

[0172] The “subjects” to which the administration is intended include, but are not limited to, human (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, e.g., mammals (e.g., primates (e.g., cynomolgus macaques, rhesus macaques), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs). In certain embodiments, the subject is human. In certain embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein.

[0173] Diseases, disorders, and conditions are used interchangeably in this specification.

[0174] As used herein, unless otherwise specified, the terms “treat,” “treating,” and “treatment” refer to actions taken while a subject is suffering from a particular disease, disorder, or condition that reduce the severity of the disease, disorder, or condition, or that delay or slow the progression of the disease, disorder, or condition ("therapeutic treatment"), and also refer to actions taken before a subject begins to suffer from a particular disease, disorder, or condition ("preventive treatment").

[0175] Generally, the “effective dose” of a compound refers to an amount sufficient to elicit a desired biological response. As will be understood by those skilled in the art, the effective dose of the compound in this invention may vary depending on factors such as the desired biological objective, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health status, and condition of the subject. The effective dose includes both therapeutic and prophylactic treatments.

[0176] Where used herein, unless otherwise specified, “therapeutic effective dose” of a compound means a dose that provides therapeutic benefit in the treatment of a disease, disorder, or condition, or that provides therapeutic benefit in the treatment of such disease, disorder, or condition. A sufficient amount to delay or minimize one or more symptoms associated with the harm or condition. The therapeutically effective dose of a compound means the amount of the therapeutic agent, alone or in combination with other treatments, that provides a therapeutic benefit in the treatment of the disease, disorder, or condition. The term “therapeutically effective dose” 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 effect of another therapeutic agent.

[0177] As used herein, unless otherwise specified, “preventive dose” of a compound means an amount sufficient to prevent or prevent the recurrence of a disease, disorder, or condition, or one or more symptoms associated with that disease, disorder, or condition. The preventive dose of a compound means the amount of the therapeutic agent, alone or in combination with other agents, that provides a preventive benefit in the prevention of the disease, disorder, or condition. The term “preventive dose” may include an amount that improves overall prevention or enhances the preventive efficacy of another preventive agent. [Modes for carrying out the invention]

[0178] Detailed description of specific embodiments of the present invention As generally described above, the present invention provides substituted oxysterols useful for preventing and / or treating a wide range of disorders (including, but not limited to, NMDA-mediated disorders). compound

[0179] In one phase, equation (A): [ka] Compounds or pharmaceutically acceptable salts thereof are provided herein, in which formula (A): R 1A and R 1B Each of them independently is hydrogen, a substituted or unsubstituted alkyl, a carbocykryl, a heterocyclyl, an aryl or heteroaryl, or R 1A and R1B They form a 3- to 8-membered ring together with the carbon atoms to which they are bonded; n is either 1 or 2; R 2A and R 2B Each of these is independently hydrogen, halo, -OR C , alkyl, alkenyl, alkynyl, aryl or heteroaryl, where R C is either hydrogen or alkyl, or R 2A and R 2B They form an oxo group together with the carbon atoms to which they are bonded, and here, R 2A and R 2B Both are not hydrogen at the same time; R 3 This includes hydrogen, alkyl, alkenyl, alkynyl or -OR A And here, R A It is alkyl; R 4 It does not exist, or it is hydrogen; and [ka] represents a single bond or a double bond, where, [ka] If one of them is a double bond, the other [ka] It is a single bond; [ka] If both are single bonds, R 4 is hydrogen; and [ka] If one of them is a double bond, R 4 It does not exist.

[0180] In some embodiments, n is 1. In other embodiments, n is 2.

[0181] In some embodiments, R 1A , R 3 and R 4 is hydrogen, and R 1B If R is an unsubstituted isopropyl, 2A and R 2B They do not form an oxo group with the carbon atoms to which they are bonded; and R 4 R does not exist, 3 is hydrogen, and R 1A and R 1B If R is -CH3, 2A It is not -CH3, and R 2B It is not -OH.

[0182] In some embodiments, R 4 R does not exist, 2A is -OH, and R 2B is hydrogen or -CF3, and R 1A and R 1B If R is -CH3, 3 is not hydrogen; and R 1A and R 1B is -CH3, and R 3 If R is hydrogen, 2A and R 2B These do not form oxo groups with the carbon atoms to which they are bonded.

[0183] In some embodiments, the compound of formula (A) is formula (AI): [ka] It is a compound of [the compound].

[0184] In some embodiments, the compound of formula (A) is of formula (A-II): [ka] It is a compound of [the compound].

[0185] In some embodiments, the compound of formula (A) is of formula (A-III):

Chemical formula

[0186] In some embodiments, the compound of formula (A) is of formula (A-IV), (A-V) or (A-VI):

Chemical formula

[0187] In some embodiments, the compound of formula (A) is of formula (A-VII), (A-VIII) or (A-IX):

Chemical formula

[0188] In some embodiments, the compound of formula (A) is of formula (A-X):

Chemical formula

[0189] In some embodiments, the compound of formula (A) is of formula (A-XII) [Chemical formula] [wherein, R' is alkyl or -OR A and here, R A is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5 or 6; and m is 0, 1, 2 or 3] is a compound.

[0190] In some embodiments, R 4 is absent, one of R 2A and R 2B is -OH, and R 3 is not hydrogen.

[0191] In some embodiments, each of R 1A and R 1B is independently unsubstituted or substituted alkyl (e.g., haloalkyl, alkoxyalkyl, -CH3, -CH2CH3, -CH(CH3)2, -CF3 or -CH2OCH3).

[0192] In other embodiments, each of R 1A and R 1B is independently substituted alkyl (e.g., haloalkyl). In some embodiments, R 1A and R 1B are alkyl (e.g., unsubstituted or substituted alkyl (e.g., -CH3)). In some embodiments, R 1A and R 1B are -CH3.

[0193] In some aspects, R 1A is -CF3 or -CH2OCH3.

[0194] In other aspects, R 1A is hydrogen, and R 1B is alkyl, carbocyclic, heterocyclic, aryl or heteroaryl.

[0195] In some embodiments, R1A and R 1B These atoms, together with the carbon atoms to which they are bonded, form a 3- to 8-membered ring.

[0196] In some situations, R 1A is a substituted alkyl or unsubstituted C2-C6 alkyl, and R 1B These are substituted or unsubstituted C1-C6 alkyl groups.

[0197] In some embodiments, R 2A and R 2B Each of them is independently an alkyl (e.g., substituted or unsubstituted alkyl). In some aspects, R 2A and R 2B Each of these is independently -F.

[0198] In other embodiments, R 2A and R 2B is -CH3, R 3 is alkyl, alkenyl, alkynyl or -OR A And here R A is alkyl. In some other embodiments, R 2A and R 2B Each of them is independently a hydrogen atom, and R 3 is an alkyl group (e.g., substituted or unsubstituted alkyl group).

[0199] In some embodiments, R 3 This includes alkyl (e.g., substituted or unsubstituted alkyl), alkenyl, alkynyl, or -OR A And here, R A is alkyl. In other embodiments, R 3 is an alkyl group (e.g., substituted or unsubstituted alkyl group).

[0200] In one phase, equation (B): [ka] Compounds or pharmaceutically acceptable salts thereof are provided herein, in formula (B): R 1A and R 1B Each of them independently is hydrogen, a substituted or unsubstituted alkyl, a carbocykryl, a heterocyclyl, an aryl or heteroaryl, or R 1A and R 1B They form a 3- to 8-membered ring together with the carbon atoms to which they are bonded; n is either 1 or 2; R 2A and R 2B Each of these is independently hydrogen, halo, -OR C , alkyl, alkenyl, alkynyl, aryl or heteroaryl, where R C is either hydrogen or alkyl, or R 2A and R 2B They form an oxo group together with the carbon atoms to which they are bonded, and here, R 2A and R 2B Both are not hydrogen at the same time; R 3 is alkyl, alkenyl, alkynyl or -OR A And here, R A It is alkyl; R 4 It does not exist, or it is hydrogen; and [ka] represents a single bond or a double bond, where, [ka] If one of them is a double bond, the other [ka] It is a single bond; [ka] If both are single bonds, R 4 is hydrogen; and [ka] If one of them is a double bond, R 4 It does not exist.

[0201] In some embodiments, n is 1. In other embodiments, n is 2.

[0202] In some embodiments, the compound of formula (B) is of formula (BI): [ka] It is a compound of [the compound].

[0203] In some embodiments, the compound of formula (B) is formula (B-II): [ka] It is a compound of [the compound].

[0204] In some embodiments, the compound of formula (B) is of formula (B-III): [ka] It is a compound of [the compound].

[0205] In some embodiments, the compound of formula (B) is (B-IV), (BV), or (B-VI): [ka] [In the formula, R 2C is hydrogen or alkyl, and R 3 is alkyl, alkenyl, alkynyl or -OR A And here, R A It is an alkyl compound.

[0206] In some embodiments, the compound of formula (B) is (B-VII), (B-VIII), or (B-IX): [Chemical formula] [In the formula, R 3 is alkyl, alkenyl, alkynyl or -OR A wherein R A is alkyl].

[0207] In some embodiments, the compound of formula (B) is of formula (B-X): [Chemical formula] [In the formula, R 3 is alkyl, alkenyl, alkynyl or -OR A wherein R A is alkyl].

[0208] In some embodiments, the compound of formula (B) is of formula (B-XII) [Chemical formula] [In the formula, R' is alkyl or -OR A wherein R A is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5 or 6; and m is 0, 1, 2 or 3].

[0209] In some embodiments, each of R 1A and R 1B is independently unsubstituted or substituted alkyl (e.g., haloalkyl, alkoxyalkyl, -CH3, -CH2CH3, -CH(CH3)2, -CF3 or -CH2OCH3).

[0210] In other embodiments, each of R 1A and R 1B is independently substituted alkyl (e.g., haloalkyl). In some embodiments, R 1A and R 1Bis an alkyl group (e.g., unsubstituted or substituted alkyl group (e.g., -CH3)). In some embodiments, R 1A and R 1B It is -CH3.

[0211] In some situations, R 1A It is either -CF3 or -CH2OCH3.

[0212] In other situations, R 1A is hydrogen, R 1B These are alkyl, carbocyrill, heterocyclyl, aryl, or heteroaryl compounds.

[0213] In some embodiments, R 1A and R 1B These atoms, together with the carbon atoms to which they are bonded, form a 3- to 8-membered ring.

[0214] In some situations, R 1A is a substituted alkyl or unsubstituted C2-C6 alkyl, and R 1B These are substituted or unsubstituted C1-C6 alkyl groups.

[0215] In some embodiments, R 2A and R 2B Each of them is independently an alkyl (e.g., substituted or unsubstituted alkyl). In some aspects, R 2A and R 2B Each of these is independently -F.

[0216] In other embodiments, R 2A and R 2B is -CH3, R 3 is alkyl, alkenyl, alkynyl or -OR A And here R A is alkyl. In some other embodiments, R 2A and R 2B Each of them is independently a hydrogen atom, and R 3 is an alkyl group (e.g., substituted or unsubstituted alkyl group).

[0217] In some embodiments, R 3 This includes alkyl (e.g., substituted or unsubstituted alkyl), alkenyl, alkynyl, or -OR A And here, R A is alkyl. In other embodiments, R 3 is an alkyl group (e.g., substituted or unsubstituted alkyl group).

[0218] In one phase, equation (I): [ka] Compounds or pharmaceutically acceptable salts thereof are provided herein, in which formula (I): R 1A and R 1B Each of them independently is hydrogen, a substituted or unsubstituted alkyl, a carbocykryl, a heterocyclyl, an aryl or heteroaryl, or R 1A and R 1B They form a 3- to 8-membered ring together with the carbon atoms to which they are bonded; R 2A and R 2B Each of these is independently hydrogen, halo, -OR C , alkyl, alkenyl, alkynyl, aryl or heteroaryl, where R C is either hydrogen or alkyl, or R 2A and R 2B They form an oxo group together with the carbon atoms to which they are bonded, and here, R 2A and R 2B Both are hydrogen at the same time; R 3 This includes hydrogen, alkyl, alkenyl, alkynyl or -OR A And here, R A is alkyl; R 4 It does not exist, or it is hydrogen; and [ka] represents a single bond or a double bond, where, [ka] If one of them is a double bond, the other [ka] It is a single bond; [ka] If both are single bonds, R 4 is hydrogen; and [ka] If one of them is a double bond, R 4 It does not exist; Here, R 1A , R 3 and R 4 is hydrogen, and R 1B If R is an unsubstituted isopropyl, 2A and R 2B They do not form an oxo group with the carbon atoms to which they are bonded; and R 4 R does not exist, 3 is hydrogen, and R 1A and R 1B If R is -CH3, 2A It is not -CH3, and R 2B It is not -OH.

[0219] In some embodiments, R 1A , R 3 and R 4 is hydrogen, R 1B It is unsubstituted isopropyl, and R 2A and R 2B These do not form oxo groups with the carbon atoms to which they are bonded.

[0220] In some embodiments, R 4 It does not exist, R 3 is hydrogen, R 1Aand R 1B is -CH3, R 2A It is not -CH3, and R 2B It is not -OH.

[0221] In some embodiments, the compound of formula (I) is formula (IA): [ka] It is a compound of [the compound].

[0222] In some embodiments, the compound of formula (I) is of formula (IB): [ka] It is a compound of [the compound].

[0223] In some embodiments, the compound of formula (I) is of formula (IC): [ka] It is a compound of [the compound].

[0224] In some embodiments, the compound of formula (I) is formula (IE), (IF), or (IG): [ka] [In the formula, R 2C is hydrogen or alkyl, and R 3 is alkyl, alkenyl, alkynyl or -OR A And here, R A It is an alkyl compound.

[0225] In some embodiments, the compound of formula (I) is formula (IH), (II), or (IJ): [ka] [In the formula, R 3 is alkyl, alkenyl, alkynyl or -OR AAnd here, R A It is an alkyl compound.

[0226] In some embodiments, the compound of formula (I) is formula (IK): [ka] [In the formula, R 3 is alkyl, alkenyl, alkynyl or -OR A And here, R A It is an alkyl compound.

[0227] In some embodiments, the compound of formula (I) is of formula (IM) [ka] [In the formula, R' is alkyl or -OR A And here, R A It is a compound of [where is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, or 3].

[0228] In some embodiments, R 1A and R 1B Each of these is independently an unsubstituted or substituted alkyl group (e.g., unsubstituted or substituted -CH3, -CH2CH3, -CH(CH3)2, -CF3, or -CH2OCH3).

[0229] In some embodiments, R 1A and R 1B Each of these is independently a substituted alkyl group (e.g., a haloalkyl group).

[0230] In some embodiments, R 1A It is either -CF3 or -CH2OCH3.

[0231] In some embodiments, R 1A and R 1Bis an alkyl group (e.g., unsubstituted or substituted alkyl group (e.g., -CH3)).

[0232] In some embodiments, R 1A and R 1B It is -CH3.

[0233] In some embodiments, R 1A and R 1B These atoms, together with the carbon atoms to which they are bonded, form a 3- to 8-membered ring.

[0234] In some embodiments, R 1A is hydrogen, R 1B These are alkyl, carbocyrill, heterocyclyl, aryl, or heteroaryl compounds.

[0235] In some embodiments, R 1A R is a substituted alkyl or an unsubstituted C2-C6 alkyl, 1B These are substituted or unsubstituted C1-C6 alkyl groups.

[0236] In some embodiments, R 2A and R 2B Each of them is independently an alkyl group (e.g., substituted or unsubstituted alkyl group).

[0237] In some embodiments, R 2A and R 2B Each of these is independently -F.

[0238] In some embodiments, R 2A and R 2B is -CH3, R 3 is alkyl, alkenyl, alkynyl, or -OR A And here R A It is alkyl.

[0239] In some embodiments, R 2A and R 2B is -F.

[0240] In some embodiments, R 3 This includes alkyl (e.g., substituted or unsubstituted alkyl), alkenyl, alkynyl, or -OR A And here R A It is alkyl.

[0241] In some embodiments, R 3 This refers to alkyl groups (e.g., substituted or unsubstituted alkyl groups). )

[0242] In some embodiments, R 2A and R 2B Each of them is independently hydrogen, and R 3 is an alkyl group (e.g., substituted or unsubstituted alkyl group).

[0243] In one phase, equation (II): [ka] Compounds or pharmaceutically acceptable salts thereof are provided herein, in formula (II): R 1A and R 1B Each of them independently is hydrogen, a substituted or unsubstituted alkyl, a carbocykryl, a heterocyclyl, an aryl or heteroaryl, or R 1A and R 1B They form a 3- to 8-membered ring together with the carbon atoms to which they are bonded; R 2A and R 2B Each of these is independently hydrogen, halo, -OR C , alkyl, alkenyl, alkynyl, aryl or heteroaryl, where R C is either hydrogen or alkyl, or R 2A and R 2B They form an oxo group together with the carbon atoms to which they are bonded, and here, R 2A and R 2B Both are not hydrogen at the same time; R 3 This includes hydrogen, alkyl, alkenyl, alkynyl or -OR A And here, R A It is alkyl; R 4 It does not exist, or it is hydrogen; and [ka] represents a single bond or a double bond, where, [ka] If one of them is a double bond, the other [ka] It is a single bond; [ka] If both are single bonds, R 4 is hydrogen; and [ka] If one of them is a double bond, R 4 It does not exist; However, R 4 R does not exist, 2A is -OH, and R 2B is hydrogen or -CF3, and R 1A and R 1B If R is -CH3, 3 It is not hydrogen; and R 1A and R 1B is -CH3, and R 3 If R is hydrogen, 2A and R 2B These do not form oxo groups with the carbon atoms to which they are bonded.

[0244] In some embodiments, R 4 It does not exist, R 2A and R 2BOne of them is -OH, and R 3 It is not hydrogen.

[0245] In some embodiments, the compound of formula (II) is formula (II-A): [ka] It is a compound of [the compound].

[0246] In some embodiments, the compound of formula (II) is formula (II-B): [ka] It is a compound of [the compound].

[0247] In some embodiments, the compound of formula (II) is formula (II-C): [ka] It is a compound of [the compound].

[0248] In some embodiments, the compound of formula (II) is formula (II-D): [ka] It is a compound of [the compound].

[0249] In some embodiments, the compound of formula (II) is (II-E), (II-F), or (II-G): [ka] [In the formula, R 2C is hydrogen or alkyl (e.g., substituted or unsubstituted alkyl), and R 3 [ is a compound of alkyl (e.g., substituted or unsubstituted alkyl)].

[0250] In some embodiments, the compound of formula (II) is (II-H), (II-I), or (II-J): [ka] [ka] [In the formula, R 3 is alkyl, alkenyl, alkynyl or -OR A And here, R A It is an alkyl compound.

[0251] In some embodiments, the compound of formula (II) is (II-K) [ka] [In the formula, R' is alkyl or -OR A And here, R A It is a compound of [where is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, or 3].

[0252] In some embodiments, R 1A and R 1B Each of these can independently be an unsubstituted or substituted alkyl group (e.g., haloalkyl, alkoxyalkyl, -CH3, -CH2CH3, It is -CH(CH3)2, -CF3, or -CH2OCH3.

[0253] In some embodiments, R 1A and R 1B Each of these is independently a substituted alkyl group (e.g., a haloalkyl group).

[0254] In some embodiments, R 1A It is either -CF3 or -CH2OCH3.

[0255] In some embodiments, R 1A and R 1B is an alkyl group (e.g., unsubstituted or substituted alkyl group (e.g., -CH3)).

[0256] In some embodiments, R 1A and R 1B It is -CH3.

[0257] In some embodiments, R 1A and R 1B These atoms form a ring together with the carbon atoms to which they are bonded.

[0258] In some embodiments, R 1A is hydrogen, R 1B These are alkyl, carbocyrill, heterocyclyl, aryl, or heteroaryl compounds.

[0259] In some embodiments, R 2A and R 2B Each of them is independently an alkyl group (e.g., substituted or unsubstituted alkyl group).

[0260] In some embodiments, R 3 is an alkyl group (e.g., substituted or unsubstituted alkyl group).

[0261] In some embodiments, R 2A and R 2B Each of them is independently hydrogen, and R 3 is an alkyl group (e.g., substituted or unsubstituted alkyl group).

[0262] In some embodiments, R 2A and R 2B Each of these is independently -F.

[0263] In some embodiments, R 2A and R 2B is -CH3, R 3 is alkyl, alkenyl, alkynyl, or -OR A And here R A It is alkyl.

[0264] In some embodiments, R 2A and R2B is -F.

[0265] In some embodiments, R 1A R is a substituted alkyl or an unsubstituted C2-C6 alkyl, 1B These are substituted or unsubstituted C1-C6 alkyl groups.

[0266] In some aspects, the compound is given by formula (III): [ka] [In the formula, R 1A and R 1B Each of them is alkyl; R 2A and R 2B Each of them independently contains hydrogen, -OR C or alkyl, where R C is either hydrogen or alkyl, or R 2A and R 2B They form an oxo group together with the carbon atoms to which they are bonded, and here, R 2A and R 2B Both simultaneously Not hydrogen; R 3 It is alkyl; R 4 It does not exist, or it is hydrogen; and [ka] represents a single bond or a double bond, where, [ka] If one of them is a double bond, the other [ka] It is a single bond; [ka] If both are single bonds, R4 is hydrogen; and [ka] If one of them is a double bond, R 4 It is a compound of [that which does not exist] or a pharmaceutically acceptable salt thereof.

[0267] In some situations, R 1A and R 1B Each of these is -CH3.

[0268] In some situations, R 2A and R 2B These atoms form an oxo group together with the carbon atoms to which they are bonded.

[0269] In some situations, R 3 It is -CH2CH3.

[0270] In some situations, R 2A is -OH, and R 2B H is H.

[0271] In some situations, R 2A is -CH3, R 2B H is H.

[0272] In some situations, R 2A is -OH, and R 2B It is -CH3.

[0273] In some situations, R 1A It is -CF3.

[0274] In alternative embodiments, the compounds described herein may also include one or more isotopic substitutions. For example, hydrogen is 2 H (D or Deuterium) or 3 It could be H (T or tritium); carbon, for example, 13 C or 14It could be C; oxygen, for example, 18 It could be O; nitrogen, for example, 15 It could be N, etc. In other embodiments, a specific isotope (for example, 3 H, 13 C, 14 C, 18 O or 15 N) may correspond to at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of the element occupying a particular site of the compound. Pharmaceutical composition

[0275] In another aspect, the present invention relates to a pharmaceutically acceptable carrier and a pharmaceutically acceptable composition containing an effective amount of a compound of formula (A), formula (B), formula (I), formula (II), or formula (III). To provide goods.

[0276] When used as pharmaceuticals, the compounds provided herein are typically administered in the form of pharmaceutical compositions. Such compositions may be prepared by methods well known in the pharmaceutical field and may contain at least one active compound.

[0277] In one embodiment, with respect to a pharmaceutical composition, the carrier is a parenteral carrier, an oral carrier, or a topical carrier.

[0278] The present invention also relates to compounds of formula (A), formula (B), formula (I), formula (II), or formula (III), or pharmaceutically active compositions thereof, for use as pharmaceuticals or pharmacopoeias.

[0279] Typically, the compounds provided herein are administered in effective doses. The actual amount of compound administered is typically determined by a physician in light of the relevant circumstances, including the symptoms being treated, the chosen route of administration, the specific compound administered, the individual patient's age, weight and response, and the severity of the patient's symptoms.

[0280] The pharmaceutical compositions provided herein may 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 may be formulated as either injectable or oral compositions, or as ointments, lotions, or patches (all for transdermal administration).

[0281] Compositions for oral administration may take the form of bulk liquid solutions or suspensions or bulk powders. However, more generally, compositions are provided in unit dosage forms to facilitate precise administration. The term “unit dosage form” refers to a physically discontinuous unit suitable as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect together with suitable pharmaceutically acceptable excipients. Typical unit dosage forms include pre-measured and pre-filled ampoules or syringes for liquid compositions, or pills, tablets, capsules, etc., for solid compositions. In such compositions, the compound is usually present in small amounts (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various vehicles or carriers and processing aids that help form the desired dosage form.

[0282] Liquid forms suitable for oral administration include buffers, suspensions, and pre-formulations (dispensing The solid form may contain a suitable aqueous or non-aqueous vehicle containing agents, colorants, fragrances, etc. The solid form may contain, for example, any of the following components or compounds of similar properties: binders (e.g., microcrystalline cellulose, tragacanth gum, or gelatin); excipients (e.g., starch, or lactose); disintegrants (e.g., alginic acid, Primogel, or corn starch); lubricants (e.g., magnesium stearate); lubricants (e.g., colloidal silicon dioxide); sweeteners (e.g., sucrose, or saccharin); or flavorings (e.g., peppermint, methyl salicylate, or orange flavor).

[0283] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As is conventional, the active compound in such compositions is typically a trace component, often about 0.05–10% by weight, with the remainder being an injectable carrier, etc.

[0284] A transdermal composition typically contains one or more active ingredients in a range of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 The active ingredient is formulated as a topical ointment or cream, containing an amount in the range of approximately 10% by weight, and more preferably in the range of approximately 0.5 to approximately 15% by weight. When formulated as an ointment, the active ingredient is typically miscible with a paraffin ointment base or a water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream, for example, containing an oil-in-water cream base. Such transdermal formulations are well known in the art and generally contain the active ingredient or further components that enhance the skin penetration or stability of the formulation. All such known transdermal formulations and components are included within the scope provided herein.

[0285] The compounds provided herein may also be administered by transdermal devices. Therefore, transdermal administration can be achieved using reservoir-type, porous membrane-type, or solid matrix-type patches.

[0286] The components described above for orally, injectably, or topically administered compositions are merely representative. Other materials and processing methods are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania (as incorporated herein by reference).

[0287] The components described above for orally, injectably, or topically administered compositions are merely representative. Other materials and processing methods are shown in Part 8 of Remington's The Science and Practice of Pharmacy, 21st edition, 2005, published by Lippincott Williams & Wilkins (incorporated herein by reference).

[0288] The compounds of the present invention may also be administered in sustained-release form or via sustained-release drug delivery systems. A description of typical sustained-release materials can be found in Remington's Pharmaceutical Sciences.

[0289] The present invention also relates to pharmaceutically acceptable formulations of compounds of formula (A), formula (B), formula (I), formula (II), or formula (III). In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, each comprising 6, 7, and 8 α-1,4-linked glucose units, respectively, with one or more substituents optionally on the linked sugar moiety (including, but not limited to, methylation, hydroxyalkylation, acylation, and sulfoalkyl ether substitution). In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, for example, a sulfobutyl ether β-cyclodextrin, also known as Captisol®. See, for example, U.S. Patent No. 5,376,645. In certain embodiments, the formulation comprises hexapropyl-β-cyclodextrin. In a further specific embodiment, the formulation comprises hexapropyl-β-cyclodextrin (e.g., 10-50% in water).

[0290] The present invention also relates to pharmaceutically acceptable acid addition salts of compounds of formula (A), formula (B), formula (I), formula (II), or formula (III). Acids that can be used to prepare pharmaceutically acceptable salts are those that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions (e.g., hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, p-toluenesulfonate, etc.).

[0291] The following examples of formulations illustrate typical pharmaceutical compositions that can be prepared according to the present invention. However, the present invention is not limited to the following pharmaceutical compositions.

[0292] Exemplary Formulation 1 - Tablets: Compounds of formula (A), formula (B), formula (I), formula (II), or formula (III), or pharmaceutically acceptable salts thereof, can be mixed as dry powders with a dry gelatin binder in approximately a 1:2 weight ratio. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg of the active compound per tablet) using a tablet press.

[0293] Exemplary Formulation 2 - Capsules: A compound of formula (A), formula (B), formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, may be mixed with a starch diluent in approximately a 1:1 weight ratio as a dry powder. The mixture is filled into 250 mg capsules (125 mg of the active compound per capsule).

[0294] Exemplary Formulation 3 - Liquid: A compound of formula (A), formula (B), formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof (125 mg), may be mixed with sucrose (1.75 g) and xanthan gum (4 mg). The resulting mixture is passed through a No. 10 mesh US sieve and then mixed with a pre-prepared aqueous solution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89.50 mg). Sodium benzoate (10 mg), fragrance, and colorant are diluted with water and added while stirring. The total volume can then be increased to 5 mL by adding sufficient water.

[0295] Exemplary Formulation 4 - Tablets: Compounds of formula (A), formula (B), formula (I), formula (II), or formula (III), or pharmaceutically acceptable salts thereof, can be mixed as dry powders with a dry gelatin binder in approximately a 1:2 weight ratio. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg of the active compound) using a tablet press.

[0296] Exemplary Formulation 5 - Injectable Formulation: Compounds of formula (A), formula (B), formula (I), formula (II), or formula (III), or pharmaceutically acceptable salts thereof, can be dissolved or suspended in an injectable aqueous medium of sterile buffered saline at a concentration of approximately 5 mg / mL.

[0297] Exemplary Formulation 6 - Tablets: Compounds of formula (A), formula (B), formula (I), formula (II), or formula (III), or pharmaceutically acceptable salts thereof, can be mixed as dry powders with a dry gelatin binder in approximately a 1:2 weight ratio. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into 90-150 mg tablets (30-50 mg of the active compound per tablet) using a tablet press.

[0298] Exemplary Formulation 7 - Tablets: Compounds of formula (A), formula (B), formula (I), formula (II), or formula (III), or pharmaceutically acceptable salts thereof, can be mixed as dry powders with a dry gelatin binder in approximately a 1:2 weight ratio. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into 30-90 mg tablets (10-30 mg of the active compound per tablet) using a tablet press.

[0299] Exemplary Formulation 8 - Tablets: Compounds of formula (A), formula (B), formula (I), formula (II), or formula (III), or pharmaceutically acceptable salts thereof, can be mixed as dry powders with a dry gelatin binder in approximately a 1:2 weight ratio. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into 0.3 to 30 mg tablets (0.1 to 10 mg of the active compound per tablet) using a tablet press.

[0300] Exemplary Formulation 9 - Tablets: Compounds of formula (A), formula (B), formula (I), formula (II), or formula (III), or pharmaceutically acceptable salts thereof, can be mixed as dry powders with a dry gelatin binder in approximately a 1:2 weight ratio. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into 150-240 mg tablets (50-80 mg of the active compound per tablet) using a tablet press.

[0301] Exemplary Formulation 10 - Tablets: Compounds of formula (A), formula (B), formula (I), formula (II), or formula (III), or pharmaceutically acceptable salts thereof, can be mixed as dry powders with a dry gelatin binder in approximately a 1:2 weight ratio. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into 270-450 mg tablets (90-150 mg of the active compound per tablet) using a tablet press.

[0302] The dose levels of the injectable agent range from approximately 0.1 mg / kg / hour to at least 10 mg / kg / hour, all over a period of approximately 1 to 120 hours, particularly 24 to 96 hours. A preloading bolus of approximately 0.1 mg / kg to 10 mg / kg or more may also be administered to achieve an appropriate steady-state level. The maximum total dose is not expected to exceed approximately 2 g / day for human patients weighing 40-80 kg.

[0303] For the prevention and / or treatment of long-term conditions, the regimen typically lasts for months or even years; therefore, for patient convenience and tolerance, oral administration is preferred. In the case of oral administration, a typical regimen involves 1 to 5 doses per day, particularly 2 to 4 doses, and usually 3 doses. When using these dosing patterns, each dose yields approximately 0.01 to approximately 20 mg / kg of the compound provided herein, with preferred doses yielding approximately 0.1 to approximately 10 mg / kg, particularly approximately 1 to approximately 5 mg / kg.

[0304] Transdermal administration is generally chosen to deliver blood levels similar to or lower than those achieved using injectable administration.

[0305] When used to prevent the development of CNS disorders, the compounds provided herein may typically be administered to subjects at risk of developing the symptoms at the dosage levels described above, with the advice and supervision of a physician. Subjects at risk of developing specific symptoms generally include those with a family history of the symptoms or those identified by genetic testing or screening as particularly susceptible to developing the symptoms. Treatment method and use

[0306] The compounds of the present invention (e.g., compounds of formula (A), formula (B), formula (I), formula (II), or formula (III), and their pharmaceutically acceptable salts) are generally designed to modulate NMDA function as described herein, and therefore to act as oxysterols for the treatment and prophylaxis of, for example, CNS-related conditions in a subject. In some embodiments, the compounds described herein (e.g., compounds of formula (A), formula (B), formula (I), formula (II), or formula (III), and their pharmaceutically acceptable salts) are generally designed to permeate the blood-brain barrier as described herein (e.g., designed to be transported across the blood-brain barrier). Modulation, as used herein, means, for example, inhibition or synergy of NMDA receptor function. In certain embodiments, compounds of formula (A), formula (B), formula (I), formula (II), or formula (III), or pharmaceutically acceptable salts thereof, act as negative allosteric modulators (NAMs) of NMDA and inhibit NMDA receptor function. In certain embodiments, the present invention (e.g., compounds of formula (A), formula (B), formula (I), formula (II), or formula (III), or pharmaceutically acceptable salts thereof) act as positive allosteric modulators (NAMs) of NMDA. They act as allosteric modulators (PAMs) and synergistically enhance NMDA receptor function. In certain embodiments, compounds of formula (A), formula (B), formula (I), formula (II), or formula (III) or their pharmaceutically acceptable salts block or mitigate the synergistic or inhibitory effects of naturally occurring substrates on NMDA receptor function. Such compounds do not act as either negative or positive allosteric modulators (PAMs) of NMDA. In some embodiments, this disorder is cancer. In some embodiments, this disorder is diabetes. In some embodiments, this disorder is sterol synthesis disorder. In some embodiments, this 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, or colitis. In some embodiments, this disorder is inflammatory bowel disease.

[0307] Exemplary conditions related to NMDA regulation 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 GI, anal disorders (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas), colon polyps, cancer, colitis), and CNS conditions (e.g., those described herein).

[0308] Exemplary conditions associated with NMDA modulation (e.g., CNS conditions) include adjustment disorders, anxiety disorders (obsessive-compulsive disorder, post-traumatic stress disorder, social phobia, generalized anxiety disorder), cognitive impairments (Alzheimer's disease and other forms of dementia (corticobasal dementia, progressive supranuclear palsy, frontotemporal dementia, primary progressive aphasia, Parkinson's disease dementia, and Lewy body dementia)), dissociative disorders, eating disorders, mood disorders (depression (e.g., postpartum depression), bipolar disorder, dysthymia, suicidal tendencies), schizophrenia or other psychotic disorders (e.g., schizoaffective psychosis), sleep disorders (e.g., insomnia), substance abuse-related disorders, personality disorders (e.g., obsessive-compulsive personality disorder), and autism spectrum disorders (including those involving mutations in Shank group proteins (e.g., Shank3)). This includes, but is not limited to, neurodevelopmental disorders (such as Rett syndrome), multiple sclerosis, sterol synthesis disorders, Smith-Lemle-Oppitz syndrome, pain (such as acute pain, chronic pain, and neuropathic pain), paroxysmal disorders (such as status epilepticus and monogenic epilepsy, e.g., Dravet disease, tuberous sclerosis complex (TSC), and infantile spasms), stroke, subarachnoid hemorrhage, intracerebral hemorrhage, cerebral ischemia, traumatic brain injury, motor disorders (such as Huntington's disease and Parkinson's disease), attention deficit disorder, attention deficit hyperactivity disorder, metabolic encephalopathy (such as phenylketonuria), postpartum psychosis, syndromes associated with high-titer anti-NMDA receptor antibodies (such as anti-NMDA receptor encephalitis), neurodegenerative disorders, neuroinflammation, neuropsychiatric lupus, Niemann-Pick C disorder, and tinnitus.

[0309] In certain embodiments, the compounds of the present invention, such as those of formula (A), formula (B), formula (I), formula (II), or formula (III), or their pharmaceutically acceptable salts, may be used to induce sedation or anesthesia.

[0310] In certain embodiments, compounds of formula (A), formula (B), formula (I), formula (II), or formula (III) or pharmaceutically acceptable salts thereof are effective in treating adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, social phobia, and generalized anxiety disorder), cognitive disorders (including Alzheimer's disease and other forms of dementia such as corticobasal dementia, progressive supranuclear palsy, frontotemporal dementia, primary progressive aphasia, Parkinson's disease dementia, and Lewy body dementia). Disorders include: dissociative disorders, eating disorders, mood disorders (depression (e.g., postpartum depression), bipolar disorder, dysthymic disorder, suicidal tendencies), schizophrenia or other psychotic disorders (e.g., schizoaffective psychosis), sleep disorders (e.g., insomnia), substance abuse-related disorders, personality disorders (e.g., obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations in Shank group proteins (e.g., Shank3)), neurodevelopmental disorders (e.g., Rett syndrome), multiple sclerosis, sterol synthesis disorders, Smith-Lemle-Oppitz syndrome, and pain (acute pain, chronic pain, and neuropathic pain). It is useful in the treatment or prevention of: paroxysmal disorders (including persistent status epilepticus and monogenic epilepsy, e.g., Dravet disease, tuberous sclerosis complex (TSC), and infantile spasms); stroke; subarachnoid hemorrhage; intracerebral hemorrhage; cerebral ischemia; traumatic brain injury; motor disorders (including Huntington's disease and Parkinson's disease); attention deficit disorder; attention deficit hyperactivity disorder; metabolic encephalopathy (including phenylketonuria); postpartum psychosis; syndromes associated with high-titer anti-NMDA receptor antibodies (including anti-NMDA receptor encephalitis); neurodegenerative disorders; neuroinflammation; neuropsychiatric lupus; Niemann-Pick C disorder; and tinnitus.

[0311] In certain embodiments, compounds of formula (A), formula (B), formula (I), formula (II), or formula (III) or pharmaceutically acceptable salts thereof are useful in the treatment or prevention of adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, social phobia, and generalized anxiety disorder), cognitive disorders (including Alzheimer's disease and other forms of dementia (including progressive supranuclear palsy, frontotemporal dementia, primary progressive aphasia, Parkinson's disease dementia, and Lewy body dementia)), substance abuse-related disorders, dissociative disorders, eating disorders, mood disorders (including depression (e.g., postpartum depression), bipolar disorder, dysthymia, and suicidal tendencies), schizophrenia or other psychotic disorders (including schizoaffective psychosis), personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations in Shank group proteins (e.g., Shank3)), or postpartum psychosis.

[0312] In certain embodiments, compounds of formula (A), formula (B), formula (I), formula (II), or formula (III) or pharmaceutically acceptable salts thereof are used to treat neurodevelopmental disorders (including Rett syndrome), multiple sclerosis, sterol synthesis disorders, Smith-Lemle-Oppitz syndrome, pain (including acute pain, chronic pain, and neuropathic pain), paroxysmal disorders (including status epilepticus and monogenic epilepsy, e.g., Dravet disease, tuberous sclerosis complex (TSC), and infantile spasms). It is useful in the treatment or prevention of epilepsy, stroke, subarachnoid hemorrhage, intracerebral hemorrhage, cerebral ischemia, traumatic brain injury, motor disorders (including Huntington's disease and Parkinson's disease), attention deficit disorder, attention deficit hyperactivity disorder, metabolic encephalopathy (including phenylketonuria), syndromes associated with high-titer anti-NMDA receptor antibodies (including anti-NMDA receptor encephalitis), neurodegenerative disorders, neuroinflammation, neuropsychiatric lupus, Niemann-Pick C disorder, or tinnitus.

[0313] In some embodiments, the compounds of the present invention, for example, compounds of formula (A), formula (B), formula (I), formula (II), or formula (III) that act as PAMs for NMDA receptor function, may be useful in the treatment or prevention of conditions including schizophrenia or other psychotic disorders (such as schizoaffective psychosis), sleep disorders (such as insomnia), autism spectrum disorders (such as those involving mutations in Shank group proteins (e.g., Shank3)), multiple sclerosis, movement disorders (such as Huntington's disease and Parkinson's disease), attention deficit disorder, attention deficit hyperactivity disorder, metabolic encephalopathy (such as phenylketonuria), postpartum psychosis, and syndromes associated with high-titer or anti-NMDA receptor antibodies (such as anti-NMDA receptor encephalitis) (e.g., CNS-related conditions).

[0314] In some embodiments, the compounds of the present invention, for example, compounds of formula (A), formula (B), formula (I), formula (II), or formula (III) that act as NAMs with NMDA receptor function, may be useful in the treatment or prevention of conditions including anxiety disorders (such as obsessive-compulsive disorder, post-traumatic stress disorder, social phobia, and generalized anxiety disorder), mood disorders (such as depression (e.g., postpartum depression), bipolar disorder, dysthymia, and suicidal tendencies), personality disorders (such as obsessive-compulsive personality disorder), neurodevelopmental disorders (such as Rett syndrome), pain (such as acute and chronic pain), paroxysmal disorders (such as status epilepticus and monogenic epilepsy, e.g., Dravet disease, tuberous sclerosis complex (TSC), and infantile spasms), stroke, traumatic brain injury, adjustment disorder, neuropsychiatric lupus, and tinnitus (e.g., CNS-related conditions).

[0315] In some embodiments, the compounds of the present invention, for example, compounds of formula (A), formula (B), formula (I), formula (II), or formula (III) that function as PAM or NAM for NMDA receptor function, may be useful in treating or preventing conditions including cognitive impairment (such as Alzheimer's disease and other forms of dementia (including progressive supranuclear palsy, frontotemporal dementia, primary progressive aphasia, Parkinson's disease dementia, and Lewy body dementia)), sterol synthesis disorders, and feeding disorders (e.g., CNS-related conditions).

[0316] In another context, a method is provided for treating or preventing brain excitability in a subject suspected of or suffering from a condition related to brain excitability, the method comprising administering to the subject an effective amount of the compound of the present invention (for example, a compound of formula (A), formula (B), formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof).

[0317] In another context, combinations of the compounds of the present invention (e.g., compounds of formula (A), formula (B), formula (I), formula (II), or formula (III), or pharmaceutically acceptable salts thereof) with other pharmacologically active agents are provided. The compounds provided herein may be administered as single activators or in combination with other agents. Combination administration may be carried out by any technique apparent to those skilled in the art (e.g., separate administration, sequential administration, simultaneous administration, and alternating administration). Movement impairment

[0318] Methods for treating motor disorders are also described herein. As used herein, “motor disorder” refers to a range of diseases and disorders associated with hyperkinetic disorders and abnormalities in the control of the muscles involved. Examples of motor disorders include, but are not limited to, Parkinson’s disease and tremor paralysis (defined especially by bradykinesia), dystonia, chorea and Huntington’s disease, ataxia, tremor (e.g., essential tremor), myoclonus and startle, tics and Tourette syndrome, restless legs syndrome, stiff person syndrome and gait disorders.

[0319] Tremors are involuntary, sometimes rhythmic, muscle contractions and relaxations that may involve vibration or spasms of one or more body parts (e.g., hands, arms, eyes, face, head, vocal cords, trunk, legs). Tremors can be caused by hereditary, degenerative, and idiopathic disorders, e.g., Wilson's disease, Parkinson's disease, and essential tremor, respectively; metabolic disorders (e.g., thyroid-parathyroid disorders, liver diseases, and hypoglycemia); peripheral neuropathy (associated with Charcot-Marie-Tooth disease, Lucy-Lévy disease, diabetes mellitus, and complex focal pain syndrome); toxin-induced disorders (nicotine, mercury, lead, CO, manganese, arsenic, toluene); and drugs (hypnotics, tricyclic antidepressants, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, etc.). This includes disorders induced by thyroid hormones (vincristine), as well as psychogenic disorders. Clinical tremors can be classified into physiological tremors, fatigue-induced physiological tremors (enhanced physiologic tremor), essential tremor syndromes (including classical essential tremor, primary orthostatic tremor, and task-specific and positional tremors), dystonic tremors, Parkinsonian tremors, cerebellar tremors, Holmes tremor (i.e., red tremor), palatal tremors, neuropathic tremors, toxic or drug-induced tremors, and psychogenic tremors. Other forms of tremor include cerebellar tremor or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, Parkinsonian tremor, physiological tremor, psychogenic tremor, or red tremor.

[0320] Cerebellar tremor, or intention tremor, is a slow, widespread tremor of the limbs that occurs after an intentional movement. Cerebellar tremors are caused by lesions or damage to the cerebellum, for example, resulting from tumors, strokes, or diseases (e.g., multiple sclerosis, hereditary degenerative disorders).

[0321] Dystonic tremors occur in individuals with dystonia, a movement disorder characterized by persistent, involuntary muscle contractions that cause twisting and repetitive movements and / or painful, abnormal postures or positions. Dystonic tremors can affect any muscle in the body. They occur irregularly and can often be relieved by complete rest.

[0322] Essential tremor, or benign essential tremor, is the most common type of tremor. Essential tremor can be mild and non-progressive in some cases, or it can be slowly progressive, starting on one side of the body but affecting both sides within three years. The hands are most frequently affected, but the head, voice, tongue, legs, and trunk can also be involved. The frequency of tremors may decrease with age, but their severity may increase. Emotional agitation, stress, fever, physical fatigue, or hypoglycemia can trigger and / or increase the severity of tremors. Symptoms generally develop over a long period, becoming visible after onset and potentially persisting.

[0323] Orthostatic tremor is characterized by rapid (e.g., above 12 Hz) rhythmic muscle contractions in the legs and trunk immediately after standing. The spasms are felt in the thighs and legs, and patients may tremble uncontrollably when asked to stand in one place. Orthostatic tremor can occur in patients with essential tremor.

[0324] Parkinsonian tremors are caused by damage to the brain structures that control movement. Often a precursor to Parkinson's disease, tremors typically manifest as a "pill-rolling" movement of the hand, but can also affect the chin, lips, legs, and trunk. The onset of Parkinsonian tremors typically begins after age 60. The movement may begin in one limb or one side of the body and progress to the other side.

[0325] Physiological tremors can occur in normal individuals and are not clinically significant. They can occur in all voluntary muscle groups. Physiological tremors can be caused by certain drugs, alcohol withdrawal, or medical conditions including hyperthyroidism and hypoglycemia. These tremors typically have a frequency of approximately 10 Hz.

[0326] Psychogenic tremors or hysterical tremors can occur at rest, during postural movements, or during active movements. Patients with psychogenic tremors may also have conversion disorder or another psychiatric disorder.

[0327] Red nuclear tremor is characterized by slow, coarse tremors that can occur at rest, in posture, and when intentional. This tremor may be associated with conditions affecting the red nucleus in classic, rare strokes of the midbrain.

[0328] Parkinson's disease affects the nerve cells in the brain that produce dopamine. Symptoms include muscle rigidity, tremors, and changes in speech and gait. Tremor paralysis is characterized by tremors, bradykinesia, rigidity, and postural instability. Tremor paralysis shares symptoms with Parkinson's disease, but it is a group of symptoms rather than a progressive neurodegenerative disease.

[0329] Dystonia is a movement disorder characterized by persistent or intermittent muscle contractions that are abnormal and often cause repetitive movements or postures. Dystonic movements can be patterned, twisting, and trembling. Dystonia is often triggered or aggravated by voluntary movement and is often associated with an overflow of muscle activation.

[0330] Chorea is a neurological disorder typically characterized by rhythmic, involuntary movements affecting the shoulders, hips, and face.

[0331] Huntington's disease is a genetic disorder that weakens nerve cells in the brain. Symptoms include uncontrolled movement, clumsiness, and balance problems. Huntington's disease can interfere with walking, speaking, and swallowing.

[0332] Ataxia refers to the loss of complete control over bodily movements and can affect fingers, hands, arms, legs, body, speech, and eye movements.

[0333] Myoclonus and startle are responses to sudden and unexpected stimuli that may be auditory, tactile, visual, or vestibular.

[0334] Tics are involuntary movements that typically begin suddenly, are short, repetitive but not rhythmic, and often mimic normal behavior, occurring outside the context of normal activity. Tics can be classified as motor tics or vocal tics; motor tics are associated with movement, while vocal tics are associated with sound. Tics can be characterized as simple or complex. For example, simple motor tics involve only a few muscles limited to a specific part of the body.

[0335] Tourette syndrome is a hereditary neuropsychiatric disorder that develops in childhood and is characterized by multiple motor tics and at least one vocal tic.

[0336] Lower limb restlessness syndrome is a neurological sensorimotor disorder characterized by an irresistible urge to move the legs while at rest.

[0337] Stiff person syndrome is a progressive motor disorder typically characterized by involuntary, painful spasms and muscle rigidity involving the lumbar spine and legs. Typically, it presents with an ankylosing gait accompanied by excessive lumbar lordosis. Characteristic abnormalities are typically observed in EMG recordings of continuous motor unit activity of the paravertebral axial muscles. A variant is "stiff-limb syndrome," which results in localized rigidity, typically affecting the distal legs and feet.

[0338] Gait disorders refer to abnormalities in the pattern or style of walking caused by neuromuscular, arthritis, or other physical changes. Gaits are classified according to a system of abnormal walking movements and include hemiplegic gait, diplegic gait, neuropathic gait, myopathy gait, Parkinson's disease-like gait, chorea-like gait, ataxic gait, and sensory gait. Mood disorder

[0339] Methods for treating mood disorders, such as clinical depression, postpartum depression or postnatal depression, perinatal depression, atypical depression, melancholic depression, psychogenic major depression, catatonic depression, seasonal affective disorder, mood swings, double depression, depressive personality disorder, relapsing brief depression, minor depressive disorder, bipolar disorder or manic-depressive disorder, depression caused by chronic conditions, treatment-resistant depression, treatment-refractory depression, suicide, suicidal ideation or suicidal behavior are also provided herein.

[0340] Clinical depression, also known as major depressive disorder (MDD), severe depression, unipolar depression, unipolar disorder, and recurrent depression, is a mental disorder characterized by pervasive and persistent depressed mood accompanied by low self-esteem and a loss of interest or pleasure in activities that are normally enjoyable. Some people with clinical depression have difficulty sleeping, become thin, generally feel agitated, and become irritable. Clinical depression affects how an individual feels, thinks, and behaves and can lead to a range of emotional and physical problems. Individuals with clinical depression may struggle to perform daily activities and may feel that life is not worth living.

[0341] Postpartum depression (PND), also known as postpartum depression (PPD), is a type of clinical depression that affects women after childbirth. Symptoms may include grief, fatigue, changes in sleep and eating habits, decreased sexual desire, crying episodes, anxiety, and irritability. In some embodiments, PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein). In some embodiments, PND is treatment-refractory depression (e.g., treatment-refractory depression as described herein).

[0342] In some embodiments, subjects with PND also experience depression or symptoms of depression during pregnancy. This depression is referred to herein as perinatal depression. In some embodiments, subjects who experience perinatal depression are at higher risk of experiencing PND.

[0343] Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anhedonia) and positivity, marked weight gain or increased appetite. Patients with AD may also have significant social impairment as a result of excessive sleepiness or somnolence (hypersomnia), heaviness in the limbs, and hypersensitivity to perceived social rejection.

[0344] Melancholic depression is characterized by a loss of pleasure from almost or all activities (anhedonic syndrome), unresponsiveness to pleasant stimuli, depressed mood that is more pronounced than feelings of grief or loss, excessive weight loss, or excessive guilt.

[0345] Psychotic major depressive disorder (PMD), or psychotic depression, refers to a major depressive episode, particularly a melancholic major depressive episode, in which an individual experiences psychotic symptoms such as delusions and hallucinations.

[0346] Catastrophic depression refers to major depressive disorder accompanied by motor and behavioral impairments and other symptoms. Individuals may become mute, enter a stupor state, become immobile, or exhibit aimless or paranoid movements.

[0347] Seasonal affective disorder (SAD) is a type of seasonal depression in which individuals experience depressive episodes that follow a seasonal pattern, typically occurring in the fall or winter.

[0348] Mood disorders refer to conditions associated with unipolar depression, where the same physical and cognitive problems are evident. They are less severe and last longer (for example, at least 2 This tendency tends to continue for years.

[0349] Bipolar disorder refers to a period of severe depression (mood disorder) that lasts for at least two years, interspersed with periods of major depression.

[0350] Depressive personality disorder (DPD) refers to a personality disorder characterized by depressive traits.

[0351] Recurrent brief depression (RBD) is a condition in which an individual experiences depressive episodes approximately once a month, each lasting for two weeks or less, typically less than two to three days.

[0352] Minor depressive disorder, or minor depression, refers to a type of depression in which at least two symptoms are present for two weeks.

[0353] Bipolar disorder, or manic-depressive disorder, is characterized by extreme mood swings, including high (manic or hypomanic) and low (depressive) moods. During manic episodes, individuals may feel or act unusually happy, energetic, or irritable. They often make impulsive decisions with little regard for consequences. Sleep needs are typically reduced. During depressive episodes, individuals may cry uncontrollably, avoid eye contact with others, and have a pessimistic outlook on life. The suicide risk for individuals with this disorder is high, over 6% over a 20-year period, and 30-40% engage in self-harm. Other mental health problems, such as anxiety disorders and substance use disorders, commonly comorbid bipolar disorder.

[0354] Depression caused by a chronic condition refers to depression that is caused by a chronic medical condition such as cancer, chronic pain, chemotherapy, or chronic stress.

[0355] Treatment-resistant depression refers to a condition in which an individual receives treatment for depression but their symptoms do not improve. For example, antidepressants or psychological counseling (psychotherapy) do not alleviate the depressive symptoms of an individual with treatment-resistant depression. In some cases, individuals with treatment-resistant depression improve their symptoms but then relapse. Treatment-resistant depression occurs in patients with depression that is resistant to standard pharmacological treatments, including tricyclic antidepressants, MAOIs, SSRIs, and double and triple reuptake inhibitors, as well as anxiolytics, and non-pharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagal stimulation, and / or transcranial magnetic stimulation).

[0356] Suicidal tendencies, suicidal ideation, and suicidal behavior refer to an individual's tendency to commit suicide. Suicidal ideation relates to thoughts about suicide or an abnormal preoccupation with suicide. The range of suicidal ideation varies greatly, for example, from momentary thoughts to broader thoughts, detailed plans, role-playing, and unsuccessful attempts. Symptoms include talking about suicide, obtaining means to commit suicide, withdrawing from social contact, constantly thinking about death, feeling trapped or hopeless about a situation, increased alcohol or drug use, engaging in dangerous or self-destructive behavior, and saying goodbye to people as if never to see them again.

[0357] Symptoms of depression include persistent feelings of anxiety or sadness, helplessness, hopelessness, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, motor challenges, loss of interest in enjoyable activities or hobbies, difficulty concentrating, low energy, low self-esteem, lack of positive thoughts or plans, excessive sleep, overeating, loss of appetite, insomnia, self-harm, suicidal thoughts, and suicide attempts. The presence, severity, frequency, and duration of symptoms can vary from case to case. The symptoms of depression and their alleviation can be assessed by a physician or psychologist (e.g., through mental health assessment). Anxiety disorder

[0358] Methods for treating anxiety disorders are provided herein. Anxiety disorder is a broad term encompassing several different forms of abnormal and pathological fears and anxieties. Current psychiatric diagnostic criteria recognize a wide range of anxiety disorders.

[0359] Generalized anxiety disorder (GPD) is a generalized chronic disorder characterized by persistent anxiety that cannot be focused on any single object or situation. People suffering from GPD experience nonspecific, persistent fears and worries, and tend to worry excessively about ordinary things. GPD is the most common anxiety disorder affecting older adults.

[0360] In panic disorder, individuals suffer from short bursts of intense fear and anxiety, often characterized by tremors, shaking, confusion, dizziness, nausea, and shortness of breath. These panic attacks (defined by APA as sudden fear or discomfort that peaks in less than 10 minutes) can last for several hours and can be triggered by stress, fear, or even exercise, although a specific cause is not always apparent. In addition to recurrent and unpredictable panic attacks, a diagnosis of phobic disorder also requires that the attacks have chronic consequences (either worry about the potential implications of the attack, persistent fear of future attacks, or significant behavioral changes related to the attack). Thus, individuals with phobic disorder experience symptoms even outside the scope of a particular panic episode. Often, unusual changes in heart rate are noticed by those suffering from panic, leading them to believe that their heart is somehow unwell or that they are about to experience another panic attack. In some cases, heightened perception of bodily functions (hypervigilance) occurs during panic attacks, in which case any perceived physiological changes are interpreted as a potentially life-threatening illness (i.e., excessive hypochondria).

[0361] Obsessive-compulsive disorder (OCD) is a type of anxiety disorder primarily characterized by recurrent obsessions (urgent, persistent, and disturbing thoughts or images) and compulsive behaviors (the urge to perform specific actions or rituals). OCD thought patterns can be linked to superstition insofar as they involve the person believing in causal relationships that do not actually exist. Often, the process is entirely illogical. For example, the compulsion to walk in a specific pattern may be used to alleviate an obsession with imminent danger. In many cases, this compulsion is not entirely inexplicable, but simply an urge to complete a neurotic-induced ritual. In a small number of cases, individuals with OCD may experience only obsessions without overt compulsions, and in even fewer, only compulsions.

[0362] One of the largest categories of anxiety disorders is phobias, which encompass all cases in which fear and anxiety are triggered by a specific stimulus or situation. Patients typically anticipate terrifying consequences from encountering their object of fear (which can range from animals, places, to bodily fluids).

[0363] Post-traumatic stress disorder, or PTSD, is an anxiety disorder resulting from a traumatic experience. Post-traumatic stress can arise from extreme situations (e.g., war, rape, hostage situations, or even major disasters). It can also result from prolonged (chronic) exposure to severe stressors (e.g., soldiers who can tolerate individual battles but cannot cope with continuous warfare). Common symptoms include flashbacks, avoidance behaviors, and depression. epilepsy

[0364] Epilepsy is a brain disorder characterized by recurrent seizures over a long period of time. Types of epilepsy include, but are not limited to, generalized epilepsy, such as childhood absence epilepsy, juvenile myoclonic epilepsy, epilepsy with grand mal seizures while awake, West syndrome, Lennox-Gastaut syndrome, and partial epilepsy, such as temporal lobe epilepsy, frontal lobe epilepsy, and benign focal epilepsy in childhood. Epilepsy occurs

[0365] Epilepsy development is a gradual process in which a normal brain develops epilepsy (a chronic condition characterized by seizures). Epilepsy development arises from nerve damage caused by an initial injury (e.g., persistent status epilepticus). Status epilepticus (SE)

[0366] Status epilepticus (SE) can include, for example, convulsive status epilepticus, such as early status epilepticus, established status epilepticus, refractory status epilepticus, and extremely refractory status epilepticus; non-convulsive status epilepticus, such as generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptic discharges; and periodic unilateral epileptic discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epilepticus seizures and can include early status epilepticus, established status epilepticus, refractory status epilepticus, and extremely refractory status epilepticus. Early status epilepticus is treated with first-line therapy. Established status epilepticus is characterized by persistent status epilepticus despite first-line treatment, and second-line treatment is initiated. Refractory status epilepticus is characterized by persistent status epilepticus despite first-line and second-line treatment, and general anesthetics are generally administered. Extremely refractory status epilepticus is characterized by persistent status epilepticus despite first-line treatment, second-line treatment, and 24 hours or more of general anesthetic treatment.

[0367] Nonconvulsive status epilepticus (NSE) can include, for example, focal NES, such as complex partial NES, simple partial NES, or micro NES; and generalized NES, such as late-onset absence NES, atypical absence NES, or typical absence NES. seizure

[0368] A seizure is a physical manifestation or change in behavior that follows an episode of abnormal electrical activity in the brain. The term “seizure” is often used interchangeably with “convulsion.” A convulsion is when a person’s body shakes rapidly and uncontrollably. During a convulsion, the person’s muscles repeatedly contract and relax.

[0369] Based on the type of behavior and brain activity, seizures are divided into two broad categories: generalized and partial (also called focal or localized). Classifying seizure types helps physicians diagnose whether or not a patient has epilepsy.

[0370] Generalized seizures are caused by electrical impulses from the entire brain, while partial seizures are caused (at least initially) by electrical impulses from a relatively small area of ​​the brain. The part of the brain that causes a seizure is sometimes called a lesion.

[0371] There are six types of generalized seizures. The most common, dramatic, and therefore most well-known is the generalized convulsion (also called a grand mal seizure). In this type of seizure, the patient loses consciousness. The patient loses consciousness and usually collapses. Following this loss of consciousness, there is a generalized rigidity of the body (called the "tonic" phase of the seizure) for 30–60 seconds, followed by severe spasms ("clonic" phase) for 30–60 seconds, after which the patient falls into deep sleep ("postictal" or after-seizure phase). During a grand severe seizure, injuries and accidents (e.g., biting the tongue and urinary incontinence) can occur.

[0372] Absence seizures cause brief (only a few seconds) periods of loss of consciousness with little or no symptoms. Patients (most frequently children) typically stop their activities and stare blankly. These seizures begin and end suddenly and can occur several times a day. Patients are usually unaware they are having seizures unless they notice they are "losing time."

[0373] Myoclonic seizures consist of sporadic spasms, usually on both sides of the body. Patients sometimes describe these spasms as short electric shocks. In severe cases, these seizures can result in dropping or involuntarily throwing objects.

[0374] Clonic seizures are recurrent, rhythmic spasms that involve both sides of the body simultaneously.

[0375] Tonic seizures are characterized by muscle rigidity.

[0376] A toneacic attack consists of a sudden decrease in muscle tone throughout the body (especially in the arms and legs) and often leads to falls.

[0377] The seizures described herein may include epileptic seizures; acute recurrent seizures; cluster seizures; serial seizures; uninterrupted seizures; persistent seizures; recurrent seizures; status epilepticus, e.g., refractory convulsive status epilepticus, nonconvulsive status epilepticus; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondary generalized seizures; atypical absence seizures; absence seizures; astonic seizures; benign Rolandic seizures; febrile seizures; affective seizures; focal seizures; laughter seizures; generalized onset seizures; infantile spasms; Jackson's seizures; generalized bilateral myoclonic seizures; multifocal seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post-traumatic seizures; microseizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures. In some embodiments, the seizures are generalized seizures associated with Dravet syndrome, Lennox-Gestaut syndrome, tuberous encephalosclerosis complex, Rett syndrome, or PCDH19 girl epilepsy. [Examples]

[0378] Example 1: Synthesis of 61 [ka] overview: [ka] Synthesis of 1 [ka] To a mixture of MePPh3Br (1.28 kg, 3.6 mol) in THF (4.5 L), t-BuOK (404 g, 3.6 mol) was added at 15°C under N2. The resulting mixture was stirred at 50°C for 30 minutes. Pregnenolone (950 g, 2.9 mol) was added gradually at a temperature below 65°C. The reaction mixture was stirred at 50°C for 1 hour. The combined mixture was quenched at 15°C with saturated NH4Cl aqueous solution (1 L). The THF layer was separated. The aqueous phase was extracted with ELISA (2 × 2 L). The combined organic phase was concentrated under vacuum to obtain a solid. The solid was further purified by grinding with refluxing MeOH / H2O (1:1, 15 L) to obtain 1 (940 g, 99%) as a solid. 1 H NMR(400MHz,CDCl3)δ 5.40-5.32(m,1H),4.85(s,1H),4.71(s,1H),3.58-3.46(m,1H),2.36-2.16(m,2H),2.08-1.94(m,2H), 1.92-1.62(m,9H),1.61-1.39(m,6H),1.29-1.03(m,4H),1.01(s,3H),0.99-0.91(m,1H),0.59(s,3H).

[0379] Synthesis of 2 [ka] To a solution of 1 (800 g, 2.54 mol) in DCM (8 L), DMP (2.14 kg, 5.08 mol) was gradually added at 35°C. The reaction mixture was stirred at 35°C for 20 minutes. The reaction mixture was filtered. The filter cake was washed with DCM (3 × 1 L). The combined organic phases were washed with saturated Na₂S₂O₃ / saturated NaHCO₃ aqueous solution (3:1, 2 × 1.5 L) and brine (1.5 L), dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain 2 (794 g, crude) as a solid, which was used directly in the next step.

[0380] 3 synthesis [ka] To a solution of BHT (1.97 kg, 8.94 mol) in toluene (1 L), AlMe3 (2.14 L, 2.0 M in toluene, 4.28 mol) was added dropwise at a temperature below 25°C under an N2 atmosphere. The resulting mixture was stirred at 25°C for 1 hour. 2 (794 g, 85% by weight, 2.16 mol) in DCM (3 L) was added at -70°C. The mixture was stirred at -70°C for 1 hour. MeMgBr (862 mL, 3.0 M in diethyl ether, 2.59 mol) was added at -70°C. The reaction mixture was stirred at -70°C for 10 minutes. The mixture was quenched with saturated criticic acid (3 L) and extracted with SiO2 (2 × 2 L). The combined organic phases were washed with brine (2 L), dried with Na2SO4, filtered, and concentrated under vacuum to obtain the residue, which was ground in MeCN (3 L) at 25°C to obtain 3 (340 g, 43%) as a solid. 1 H NMR(400MHz,CDCl3)δ 5.34-5.26(m,1H),4.85(s,1H),4.71(s,1H),2.50-2.35(m,1H),2.07-1.94(m,3H),1.91-1.84(m,1H),1.83-1.63(m,8 H),1.58-1.33(m,6H),1.27-1.13(m,3H),1.12(s,3H),1.10-1.05(m,1H),1.02(s,3H),1.00-0.92(m,1H),0.58(s,3H).

[0381] 4 synthesis [ka] 3 (100 g, 304 mmol) was dissolved in 9-BBN (1.21 L, 0.5 M in THF, 608 mmol) under N2 at 0°C. The solution was stirred at 65°C for 1 hour and then recooled to 10°C. A large amount of solid precipitated. Ethanol (279 g, 6080 mmol) and NaOH aqueous solution (304 mL, 5 M, 1520 mmol) were added dropwise to the mixture at below 10°C to obtain a clear solution. Then, hydrogen peroxide (343 g, 30% in water, 3040 mmol) was added dropwise at below 10°C. The reaction mixture was stirred at 75°C for 1 hour. After recooling to 20°C, the solid precipitated and was collected by filtration. The filter cake was washed with water (3 x 500 mL) and dried under vacuum to obtain a solid. This solid was then ground in refluxing ethanol (1.5 L) to obtain 4 (92 g, 87.6%) as a solid. 1 H NMR(400MHz,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).

[0382] 5 synthesis [ka] To a solution of 4 (124.5 g, 357 mmol) in chloroform (1 L) and pyridine (700 mL), TsCl (204 g, 1071 mmol) was added at 15°C. The mixture was stirred at 15°C for 2 hours. The mixture was concentrated under vacuum to remove most of the chloroform. The pyridine mixture was added to water (6 L). A solid was formed, which was collected by filtration and washed with water (6 × 1 L). The solid was dissolved in DCM (3.5 L), dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain 5 (163 g, 92%) as a solid. 1H NMR(400MHz,CDCl3)δ 7.78(d,J=8.0Hz,2H),7.34(d,J=8.4Hz,2H),5.29-5.28(m,1H),3.96(dd,J=3.2,9.6Hz,1H),3.79(dd,J=6.4,9.2Hz ,1H),2.45(s,3H),2.41(d,J=13.6Hz,1H),1.99-1.91(m,3H),1.77-1.39(m,11H),1.26-0.86(m,16H),0.64(s,3H).

[0383] 61 synthesis [ka] To a solution of 5 (163 g, 325 mmol) in DMF (1.7 L), KI (258 g, 1560 mmol) was added at 15°C. The mixture was stirred at 60°C for 2 hours. Then, sodium benzenesulfinate (195 g, 975 mmol) was added, and the mixture was stirred at 60°C for 2 hours. The reaction mixture was cooled to 25°C and combined with another batch from 5 (83 g). The combined mixture was poured into water (20 L), and some solid was formed. The mixture was filtered, and the filter cake was washed with water (3 × 2 L). The resulting filter cake was dissolved in DCM (5 L), washed with water (2 × 1 L) and brine (2 × 1 L), dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain the crude product as a solid, which was recrystallized in toluene (2.5 L) to obtain 61 (150 g, 65%) as a solid. The recrystallized filtrate was concentrated under vacuum to obtain crude 61 (30 g) as a solid. 1 H NMR(400MHz,CDCl3)δ 7.91(d,J=7.2Hz,2H),7.69-7.61(m,1H),7.60-7.50(m,2H),5.28-5.27(m,1H),3.14(d,J=14.0Hz,1H),2.85(dd,J=9.6,14.0Hz,1H), 2.41(d,J=12.8Hz,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,16H),0.65(s,3H). LCMS Rt=2.057min (3.0 minutes of chromatography), 30-90 AB, 100% purity, C 29 H 41 O2S[M+H-H2O] + The MS ESI calculated value is 453, and the measured value is also 453. Example 2: Synthesis of Epoxides

[0384] [ka] To a suspension of t-BuOK (3.53 g, 31.6 mmol) in THF (30 mL), Me3SI (4.18 g, 20.5 mmol) was added under N2 at 15°C. The suspension was stirred at 15°C for 30 minutes. To the mixture, a solution of 21 (2 g, 15.8 mmol) in 10 mL of THF was added dropwise at 15°C. The mixture was stirred at 15°C for 16 hours. The mixture was quenched with saturated NH4Cl (100 mL) and extracted with ELISA (3 × 150 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under vacuum to obtain 22 (1.8 g, 81%) as a liquid. 1 H NMR(400MHz,CDCl3)δ 2.58(s,2H),1.90-1.80(m,1H),1.70-1.55(m,2H),1.54-1.45(m,3H),1.40-1.30(m,2H),1.00-0.90(m,6H). Example 3: Synthesis of 71 [ka] overview: [ka]

[0385] Synthesis of compound 4-2. To a solution of 4-1 (38 g, 101.5 mmol) in THF (400 mL), HATU (46.3 g, 121.8 mmol) and DIPEA (45.9 g, 355.2 mmol) were added at room temperature. The mixture was stirred for 1 hour, and then N,O-dimethylhydroxylamine hydrochloride (19.8 g, 203 mmol) was added. The mixture was stirred at room temperature for a further 6 hours. The reaction mixture was concentrated, poured into water, extracted with phenylethylamine, washed with water, dried over Na2SO4, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluate:PE:EA = 3:1) to obtain the desired product 4-2 (24 g, 57%) as a solid. 1 H NMR:(300MHz,CDCl3)δ:ppm 5.25(d,J=5.2Hz,1H),3.59(s,3H),3.46-3.37(m,1H),3.07(s,3H),2.70(s,1H),2.40-2.09(m,4H),1.92-1.63(m,6H),1. 44-1.33(m,6H),1.29-1.15(m,3H),1.11-0.93(m,5H),0.90(s,3H),0.85(d,J=6.4Hz,3H),0.82-0.78(m,1H),0.58(s,3H).

[0386] Synthesis of compound 4-3. To a solution of compound 4-2 (14 g, 33.52 mmol, 1.0 equivalent) in dry CH2Cl2 (600 mL), Dess Martin (28 g, 67.04 mmol, 2.0 equivalents) was gradually added at 0°C. The reaction mixture was then stirred at room temperature for 6.5 hours. TLC (PE:EA = 3:1) showed that the starting material had been completely consumed. The mixture was quenched with saturated NaHCO3 / Na2S2O3 aqueous solution = 1:3 (800 mL). The organic phase was washed with brine (500 mL), dried over Na2SO4, and the solvent was evaporated to obtain crude product 4-3 (14.0 g, 100%).

[0387] Synthesis of compound 4-4. A solution of Me3Al (50.5 mL, 101.00 mmol, 2 M in hexane) was added to a stirred solution of 2,6-di-tert-butyl-4-methylphenol (44.4 g, 202 mmol) in toluene (200 mL), and then a freshly prepared solution of MAD (101 mmol, 3.0 equivalents) in toluene was prepared by stirring at room temperature for 1 hour. To this solution, a solution of 4-3 (14.0 g, 33.7 mmol, 1.0 equivalent) in toluene (10 mL) was added dropwise under nitrogen at -78°C. The reaction mixture was then stirred for 30 minutes, and a solution of MeMgBr (33.7 mL, 101 mmol, 3.0 equivalents, 3 M in ether) was added dropwise at -78°C. The reaction mixture was warmed to 25°C and stirred at this temperature for 12 hours. TLC (PE:EA = 3:1) showed that the starting materials were completely consumed. The mixture was poured into a saturated aqueous solution of NH4Cl (200 mL) and extracted with ELISA (200 mL x 2). The combined organic phase was dried over Na2SO4, and the solvent was evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluate:PE:EA = 3:1) to obtain the pure target product (7.5 g, 52%) in powder form. 1 H NMR:(400MHz,CDCl3)δ 5.30(d,J=5.2Hz,1H),3.69(s,3H),3.17(s,3H),2.50-2.30(m,3H),2.05-1.70(m,7H),1.52-1.30(m,9H),1.20-0.90(m,15H),0.68(s,3H).

[0388] Synthesis of compound 3-1. To a solution of compound 4-4 (7.5 g, 17.4 mmol, 1.0 equivalent) in THF (150 mL), a solution of MeMgBr (29 mL, 87 mmol, 5.0 equivalents, 3 M in THF) was added dropwise at room temperature over 30 minutes under nitrogen. The reaction mixture was then stirred at room temperature for 12 hours. TLC (PE:EA = 1:1) showed that the starting material had been completely consumed. The mixture was poured into a saturated aqueous solution of NH4Cl (200 mL) and extracted with SiO2 (150 mL x 2). The combined organic phase was dried over Na2SO4, and the solvent was evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluate:PE:EA = 4:1) to obtain product 3-1 (5.2 g, 77%) as a powder. 1 H NMR:(400MHz,CDCl3)δ 5.30(d,J=5.2Hz,1H),2.50-2.30(m,3H),2.14(s,3H)2.03-1.93(m,3H),1.87-1.68(m,4H),1.60-1.18(m, 12H),1.12(s,3H),1.11-1.03(m,1H),1.01(s,3H),1.00-0.94(m,1H),0.91(d,J=6.4Hz,3H),0.68(s,3H).

[0389] A combination of 3 and 2. To a suspension of 3-1 (400 mg, 1.035 mmol) and CsF (76 mg) in toluene / THF (20 mL, 8 / 1), TMSCF3 (1.53 mL, 10.35 mmol) was added, and the mixture was stirred at room temperature under nitrogen at 20°C. TLC (petroleum ether:ethyl acetate = 3 / 1) showed that the starting materials were completely consumed. A solution of TBAF (6.8 mL, 1 M in THF) was added, and the mixture was stirred at room temperature for 4 hours. The mixture was diluted with MTBE (200 mL), washed with saturated NaHCO3 aqueous solution (30 mL x 3), and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluate:petroleum ether:ethyl acetate = 20:1) to obtain 3-2 (220 mg, 46%) as a solid. 1H NMR:(400MHz,CDCl3)δ 5.31(d,J=2.0Hz,1H),2.44-2.41(m,1H),2.04-1.96(m,3H),1.81-1.67(m,5H),1.65-1.39(m,11H),1.34-1.32 (m,3H),1.31-1.25(m,1H),1.21-1.10(m,3H),1.12-0.98(m,4H),0.96(s,3H),0.98-0.90(m,4H),0.68(s,3H.)

[0390] Synthesis of compound 71. Compound 3-2 (1.2 g, 2.63 mmol) was separated by SFC to obtain product 71 (400 mg). 1 H NMR(71):(400MHz,CDCl3)δ 5.32(d,J=4.0Hz,1H),2.50-2.40(m,1H),2.08-1.95(m,3H),1.90-0.90(m,35H),0.70(s,3H). Example 4: Synthesis of 1201 [ka] To a solution of 001-4 (50 g, 128 mmol) in DCM (800 mL), DMP (108 g, 256 mmol) was added at 30°C. The reaction mixture was stirred at 30°C for 10 minutes. Then, H2O (2.3 g, 128 mmol) was added dropwise. The reaction mixture was quenched with saturated NaHCO3 aqueous solution (500 mL) until the pH of the aqueous layer reached approximately 9. The mixture was filtered. The DCM layer was separated, and the aqueous phase was extracted with DCM (100 mL). The combined organic phases were washed with saturated Na2S2O3 aqueous solution (600 mL) and brine (500 mL), dried over Na2SO4, filtered, and concentrated to obtain 55 (108 g, crude) as an oily substance. The reaction was carried out twice in parallel. 1H NMR(400MHz,CDCl3)δ 5.30-5.26(m,1H),3.67(s,3H),3.30-3.22(m,1H),2.85-2.79(m,1H),2.50-2.15(m,4H),2.08-1.96(m,3H),1.90- 1.71(m,2H),1.56-1.45(m,6H),144-1.19(m,3H),1.17(s,3H),1.15-0.97(m,5H),0.96-0.88(m,3H),0.70(s,3H). [ka] To a solution of BHT (367 g, 1.67 mmol) in toluene (1000 mL), trimethylaluminum (2 M in toluene, 418 mL, 837 mmol) was added dropwise under nitrogen at 0°C. The mixture was stirred at 0°C for 30 minutes and used directly as a solution of MAD (0.59 M in toluene) without further purification. To the solution of MAD (0.59 M in toluene, 1410 mL, 837 mmol), a solution of 55 (108 g, 279 mmol) in toluene (500 mL) was added dropwise under nitrogen at -78°C. The mixture was stirred at -78°C for 30 minutes. EtMgBr (3 M in diethyl ether, 278 mL, 837 mmol, 3 M in ether) was added dropwise. The resulting mixture was stirred at -78°C for 1 hour. The reaction mixture was poured into ice-cold citric acid aqueous solution (1000 mL) and extracted with alkyl (2 × 500 mL). The combined organic layer was washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (0-20% alkyl in PE) to obtain 1201 (95 g, impure) as an oily substance. The reaction was carried out twice in parallel. 1H(400MHz,CDCl3)δ 5.30-5.26(m,1H),3.65(s,3H),2.48-2.18(m,4H),2.08-1.91(m,2H),1.90-1.76(m,4H),1.75-1.61(m,4H),1.60-1.48(m,5H),1.4 7-1.22(m,5H),1.17(s,1H),1.16-1.02(m,3H),1.01-0.96(m,2H),0.95-0.90(m,1H),0.89-0.82(m,4H),0.81-0.76(m,2H),0.67(s ,3H). Example 5: Synthesis of U6477 and U6478 [ka] overview: [ka]

[0391] Experiments with intermediate 61 can be found in Example 1 of this specification. The synthesis of the epoxide can be found in Example 2 of this specification.

[0392] 62 synthesis [ka] 5 mL of THF was mixed with n-BuLi (6.60 mL, 2.5 M in hexane, 16.5 mmol). Then, a solution of 61 (3.00 g, 6.37 mmol) in 30 mL of THF was added at -70°C. The mixture was stirred at -70°C for 1 hour. 6,6-dimethyl-1-oxaspiro[2.5]octane (1.78 g, 12.7 mmol) was added at -70°C. After stirring for another 1 hour at -70°C, the mixture was warmed to 25°C and stirred for 16 hours, and then treated with NH4Cl (50 mL, saturated aqueous solution). The mixture was extracted with siRNA (2 × 30 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated to obtain 62 (4.00 g, crude) as a solid.

[0393] 63 synthesis [ka] To a solution of 62 (4.00 g, 6.54 mmol) in MeOH (200 mL), NiCl2 (61.5 mg, 0.654 mmol) was added and the mixture was heated at 60°C. Mg powder (6.34 g, 261 mmol) was gradually added at 60°C. The mixture was stirred at 60°C for 1 hour. The mixture was quenched with HCl (200 mL, 2 M) until the reaction product became clear, and then extracted with HCl (3 × 200 mL). The combined organic phase was dried over Na2SO4, filtered, concentrated, and purified by flash column (0-15% HCl in PE) to obtain 63 (1.20 g, 39%) as a solid. 1 H NMR 63(400MHz,CDCl3)δ 5.32-5.28(m,1H),2.43-2.38(m,1H),2.05-1.56(m,9H),1.50-1.41(m,8H ),1.41-1.26(m,5H),1.26-0.94(m,15H),0.94-0.83(m,12H),0.68(s,3H).

[0394] 64 synthesis [ka] To a solution of 63 (2.00 g, 4.24 mmol) in ethyl acetate (120 mL), molecular sieves (200 mg) and t-butyl hydroperoxide (4.23 mL, 25.4 mmol, 6 M in decane) were added. The suspension was stirred at 25°C for 30 minutes under a nitrogen atmosphere, and then manganese(III) acetate dihydrate (340 mg, 1.27 mmol) was added all at once. The reaction mixture was stirred at 25°C for 48 hours. The solid was filtered off, and the filtrate was washed with Na2SO3 (200 mL) and brine (200 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0-15% ethyl acetate in DCM) to obtain 64 (1.10 g, 54%) as a solid. 1H NMR 64(400MHz,CDCl3)δ 5.66(s,1H),2.61-2.55(m,1H),2.45-2.34(m,1H),2.28-2.19(m,2H),2.08-1.7 8(m,5H),1.68-1.50(m,9H),1.50-1.08(m,21H),0.98-0.83(m,9H),0.68(s,3H).

[0395] 65 synthesis [ka] Anhydrous TMSCH2Li (0.56 M, 9.19 mL, 5.15 mmol in hexane) A solution of 64 (500 mg, 1.03 mmol) was added dropwise to a solution in THF (25 mL) under nitrogen at -40°C. The mixture was stirred at -40°C for 4 hours, then gradually warmed to 20°C, and stirred at 20°C for a further 16 hours. The reaction mixture was quenched with saturated NH4Cl (20 mL), acidified with 10% HCl (8 mL), and stirred for 2 hours. The mixture was combined with another batch (prepared from 100 mg of 64) and extracted with ÃO (3 × 20 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (0-20% ÃO in PE) to obtain 65 (220 mg, 44%) as a solid. 1 H NMR 65(400MHz,CDCl3)δ 5.79(s,1H),4.93(s,1H),4.74(s,1H),2.51-2.42(m,1H),2.19-2.00(m,4H),1.97-1.85(m,1H),1.82-1.70(m,2H),1.63-1.58(m,2) H),1.52-1.37(m,12H),1.36-1.14(m,11H),1.13(s,3H),1.09(s,3H),0.96(d,J=6.8Hz,3H),0.93(s,3H),0.87(s,3H),0.71(s,3H).

[0396] 66 synthesis [ka] To a solution of 65 (220 mg, 0.455 mmol) in THF (15 mL), 10% Pd / C (wet, 300 mg) was added. The mixture was degassed and purged with H2 three times. The mixture was stirred at 15°C for 18 hours under an H2 balloon (15 psi). The reaction mixture was filtered through a Celite pad, and the pad was washed with THF (4 × 5 mL). The combined organic solution was concentrated to obtain 66 (210 mg, crude) as a solid. LCMS 66 Rt=5.692min (7.0 minutes of chromatography), 30-90AB_7MIN_220&254_E, (Column: Xtimate C18 2.1×30mm, 3um; Mobile phase: A: Water (4L) + TFA (1.5mL) B: Acetonitrile (4L) + TFA (0.75mL); Gradient: 30%~90% B for 6 minutes, then 90% for 0.5 minutes, then 30% B for 0.5 minutes; Flow rate: 0.8mL / min; Wavelength: UV 220nm, 254nm; Oven temperature: 50℃; MS ionization: ESI; Detector: PDA, ELSD), Purity 100%, C 33 H 53 [M+H-2H2O] + The MS ESI calculated value is 449, and the measured value is also 449. SFC 66 Peak 1: Rt = 6.184 min and Peak 2 Rt = 6.969 min (10-minute chromatography), AD_3_EtOH_DEA_5_40_25ML ("Column: Chiralpak AD-3 150×4.6mm ID, 3um Mobile phase: A: CO2 B: Ethanol (0.05% DEA) Gradient: 5%~40% B for 5 minutes, then 40% for 2.5 minutes, then 5% B for 2.5 minutes Flow rate: 2.5 mL / min Column temperature: 35℃").

[0397] Combination of U6477 and U6478 [ka] Compound 66 (210 mg, 0.433 mmol) was purified by SFC (column: AD (250 mm × 30 mm, 5 μm); conditions: 0.1% NH3H2O ​​EtOH; start B: 40%; end B: 40%; gradient time (min): 100% B; retention time (min); flow rate (ml / min): 60 ml / min; injection: 200) to obtain U6477 (peak 1, 56 mg, 27%) as a solid and U6478 (peak 2, 30 mg, 14%) as a solid. Based on the characteristic HNMR of compounds 82 and U6429, the stereochemistry at C7 was assigned as follows: a) 7-α-H isomer with a singleline H-6 at high magnetic field; b) 7-β-H isomer with a doubleline H-6 at low magnetic field. U6477 1 H NMR(400MHz,CDCl3)δ 5.79(s,1H),2.50-2.42(m,1H),2.05-1.65(m,7H),1.55-1.35(m,13H),1. 34-1.05(m,16H),1.03-0.85(m,7H),0.84-0.75(m,7H),0.70-0.60(m,4H). LCMS Rt = 1.490 min (2.0 minutes of chromatography), 30-90 AB_2 MIN_E, purity 98.839%, C 33 H 53 [M+H-2H2O] + The MS ESI calculated value is 449, and the measured value is also 449. SFC Rt = 6.292 min (10 minutes of chromatography), AD₃EtOHDEA₅40 25 ml, 100% de. U6478 1 H NMR(400MHz,CDCl3)δ 5.03(s,1H),2.50-2.42(m,1H),2.05-1.95(m,2H),1.94-1.60(m,6H),1 .55-1.25(m,15H),1.24-1.05(m,12H),1.03-0.85(m,16H),0.68(s,3H). LCMS Rt=1.568min (2.0 minutes of chromatography), 30-90AB_2MIN_E, purity 100%, C 33 H 53[M+H-2H2O] + The MS ESI calculated value is 449, and the measured value is also 449. SFC Rt = 7.066 min (10 minutes of chromatography), AD3EtOHDEA54025ML, 95%de. Example 6: Synthesis of U6472 and U6473 [ka] overview: [ka]

[0398] The synthesis of 71 can be found in Example 3 of this specification.

[0399] 72 synthesis [ka] To a solution of 71 (4 g, 8.76 mmol) in ethyl acetate (200 mL), t-butyl hydroperoxide (8.74 mL, 52.5 mmol, 6 M in decane) was added. The suspension was stirred under a nitrogen atmosphere for 30 minutes, and then manganese(III) acetate dihydrate (702 mg, 2.62 mmol) was added all at once. After stirring at 30°C for 48 hours, the mixture was quenched with Na2SO3 (200 mL) and extracted with THF (2 × 100 mL). The combined organic matter was washed with Na2SO3 (200 mL) and brine (200 mL), dried with Na2SO4, filtered, and concentrated to obtain the residue, which was then ground with MeCN (60 mL) to obtain pure 72 (800 mg) as a solid. 1H NMR 72(400MHz,CDCl3)δ 5.69-5.64(m,1H),2.64-2.53(m,1H),2.51-2.36(m,1H),2.29-2.18(m,2H),2.07-1.99(m,1H),1.95-1.64(m,6H),1.6 3-1.58(m,3H),1.54-1.47(m,3H),1.45-1.25(m,8H),1.20(s,3H),1.18-1.02(m,6H),0.99-0.90(m,3H),0.69(s,3H).

[0400] 73 synthesis [ka] A solution of TMSCH2Li (18.3 mL, 8.45 mmol, 0.46 M in hexane) in THF (20 mL) was added dropwise at -40°C to a solution of 72 (800 mg, 1.69 mmol) in THF (50 mL). After addition, the resulting mixture was warmed to 30°C and stirred for 16 hours. The mixture was quenched with HCl (2 M, 100 mL) and extracted with HCl (2 × 80 mL). The combined organic phase was washed with saturated NaHCO3 (100 mL), dried over Na2SO4, filtered, concentrated, and purified by combiflush (0-20% ethyl acetate in PE) to obtain 73 (350 mg, 44%) as a solid. 1 H NMR 73(400MHz,CDCl3)δ 5.81-5.76(m,1H),4.95-4.89(m,1H),4.77-4.70(m,1H),2.50-2.41(m,1H),2.18-2.06(m,2H),2.04-2.00(m,1H),1.94-1.68(m,5H),1 .55-1.47(m,4H),1.44-1.37(m,4H),1.32(s,3H),1.30-1.11(m,10H),1.09(s,3H),0.99-0.94(m,3H),0.89-0.81(m,1H),0.71(s,3H).

[0401] 74 synthesis [ka] To a solution of 73 (350 mg, 0.746 mmol) in THF (30 mL), Pd / C (350 mg, wet) was added. The mixture was hydrogenated at 15 Psi at 30°C for 16 hours. The mixture was filtered. The filter cake was washed with THF (2 × 10 mL). The combined filtrate was concentrated and purified by combiflush (0-20% Â in PE) to obtain pure 74 (200 mg, 57%) as a solid. SFC 74 - Peak 1: Rt=3.343 min and Peak 2 Rt=4.297 min (10-minute chromatography), AD_3_EtOH_DEA_5_40_25ML (Column: Chiralpak AD-3 150×4.6mm ID, 3um Mobile phase: A: CO2 B: Methanol (0.05% DEA) Gradient: 5%~40% B for 5 minutes, then 40% for 2.5 minutes, then 5% B for 2.5 minutes Flow rate: 2.5 mL / min Column temperature: 35℃)

[0402] Combination of U6472 and U6473 [ka] A 200 mg racemic sample was separated by SFC (column: AD (250 mm × 30 mm, 5 μm), gradient: 35-35% B (A = 0.05% NH3 / H2O, B = MeOH), flow rate: 50 mL / min) to obtain U6472 (57 mg, yield 29%, peak 1) and U6473 (43 mg, yield 22%, peak 2) as solids. Based on the characteristic HNMR of compounds 82 and U6429, a) 7-α-H isomer with a singleline H-6 at high magnetic field; b) 7-β-H isomer with a doubleline H-6 at low magnetic field, the stereochemistry at C7 was assigned. U6472 1H NMR(400MHz,CDCl3)δ 5.35-5.30(m,1H),2.49-2.39(m,1H),2.06-1.90(m,3H),1.87-1.66(m,5H),1.56-1.40(m,8H),1.3 5-1.24(m,5H),1.18-1.06(m,10H),1.01(s,3H),0.97-0.91(m,3H),0.86-0.79(m,3H),0.68(s,3H). LCMS Rt=1.240 min (2.0 minutes of chromatography), 30-90AB_E, 100% purity, C 28 H 44 F3O[M+H-H2O] + The MS ESI calculated value is 453, and the measured value is also 453. SFC Rt = 3.357 min (10-minute chromatography), AD3EtOHDEA54025ml, 99.72%de. U6473 1 H NMR(400MHz,CDCl3)δ 5.06-5.00(m,1H),2.42-2.34(m,1H),2.03-1.95(m,2H),1.87-1.65(m,7H),1.56-1 .35(m,6H),1.34-1.26(m,5H),1.22-1.03(m,10H),1.00-0.91(m,10H),0.69(s,3H). LCMS Rt=1.246min (2.0 minutes of chromatography), 30-90AB_E, 100% purity, C 28 H 44 F3O[M+H-H2O] + MS ESI calculated value: 453, measured value: 453. SFC Rt = 4.300 min (10 minutes of chromatography), AD₃EtOHDEA₅40 25 ml, 99.52% de. Example 7: Synthesis of U6450 [ka]

[0403] The synthesis of U6461 can be found in Example 11 of this specification.

[0404] 82 synthesis [ka] To a solution of U6461 (100 mg, 0.232 mmol) in THF (5 mL), K-selectlide (1.16 mL, 1.16 mmol, 1 M in THF) was added dropwise at -70°C. After addition, the mixture was warmed to 0°C and stirred at this temperature for 1 hour. The mixture was quenched with saturated NH4Cl (20 mL) and extracted with siRNA (3 × 10 mL). The combined organic phase was washed with brine (2 × 20 mL), dried over Na2SO4, filtered, concentrated, and purified by combiflush (0-60% siRNA in PE) to obtain 60 mg of impure 82 as a solid, which was used directly in the next step. Based on a) the 7-α-H isomer having a singleline H-6 under high magnetic field conditions; and b) the 7-β-H isomer having a doubleline H-6 under low magnetic field conditions, the stereochemistry at C7 was assigned in comparison to compound U6429 according to the literature (Synthesis, 1987, 1002).

[0405] Synthesis of U6450 [ka] 140 mg of impure 82 was separated by SFC (column: AD (250 mm × 30 mm, 5 μm), gradient: 50-50%B (A = 0.05% NH3 / H2O, B = MeOH), flow rate: 60 mL / min) to obtain 82 (70 mg, 50%) as a solid. 1 H NMR U6450(400MHz,CDCl3)δ 5.58-5.52(m,1H),3.87-3.79(m,1H),2.46-2.38(m,1H),2.14-1.84(m,3H),1.80-1.57(m,4H),1.55-1.38(m,9H) ),1.37-1.22(m,4H),1.21-1.06(m,12H),1.04-0.97(m,4H),0.96-0.91(m,3H),0.88-0.82(m,3H),0.68(s,3H). LCMS U6450 Rt=1.108min (2.0 minutes of chromatography), 30-90AB_E, 100% purity, C 28 H 45 O[M+H-2H2O] + MS E SI calculated value: 397, measured value: 397. Example 8: Synthesis of U6437 and U6438 [ka] overview: [ka]

[0406] The synthesis of U6461 can be found in Example 11 of this specification.

[0407] 91 synthesis [ka] To a solution of U6461 (300 mg, 0.696 mmol) in THF (20 mL), MeLi (2.17 mL, 3.48 mL) was added under N2 at 0°C. The mixture was stirred at 15°C for 10 minutes and then quenched with saturated NH4Cl (30 mL). The reaction mixture was extracted with ÃA (3 × 20 mL). The combined organic phase was washed with saturated NH4Cl (50 mL), dried over Na2SO4, filtered, concentrated, and purified by combiflush (0-50% ÃA in PE) to obtain 91 (250 mg, 81%) as a solid.

[0408] Combination of U6437 and U6438 [ka] 160 mg of 91 was purified by SFC (column: AD (250 mm × 30 mm, 5 μm)) with a gradient of 50-50%B (A = 0.05% NH3 / H2O, B = MeOH) to obtain U6437 (peak 1, 80 mg, 50%) and U6438 (peak 2, 60 mg, 38%) as solids. U6437 1 H NMR (400MHz,CDCl3)δ 5.16-5.13(m,1H),2.43-2.34(m,1H),2.07-1.96(m,2H),1.91-1.61(m,5H),1.58-1.46(m,5H),1.45-1.29(m,7) H),1.26-1.18(m,9H),1.18-1.10(m,6H),1.09-1.00(m,5H),0.98-0.93(m,3H),0.88-0.82(m,3H),0.69(s,3H). LCMS Rt=1.161min (2.0 minutes of chromatography), 30-90AB_E, 100% purity, C 29 H 47 O[M+H-2H2O] + The MS ESI calculated value is 411, and the measured value is also 411. SFC Rt = 4.266 min (8 minutes of chromatography), AD_ETOH(DEA)_5_40_2.8ML_8MIN (Column: Chiralpak AD-3 100×4.6mm ID,3um Mobile phase: A:CO2 B:Ethanol (0.05%DEA) Gradient: 5% to 40% B for 4.5 minutes, then 40% for 2.5 minutes, followed by 5% B for 1 minute. Flow rate: 2.8 mL / min, Column temperature: 40°C, 100% de U6438 1 H NMR (400MHz,CDCl3)δ 5.19-5.16(m,1H),2.40-2.32(m,1H),2.08-1.98(m,2H),1.94-1.85(m,2H),1.77-1.59(m,4H),1.52-1.29(m ,13H),1.24(s,3H),1.22-1.19(m,6H),1.17-1.03(m,6H),0.99-0.92(m,6H),0.88-0.82(m,3H),0.70(s,3H). LCMS Rt=1.162min (2.0 minutes of chromatography), 30-90AB_E, purity 99.5%, C 29 H 47 O[M+H-2H2O] +The MS ESI calculated value is 411, and the measured value is also 411. SFC Rt = 5.815 min (8 minutes of chromatography), AD_ETOH(DEA)_5_40_2.8ML_8MIN (Column: Chiralpak AD-3 100×4.6mm ID, 3um Mobile phase: A:CO2 B:Ethanol (0.05%DEA) Gradient: 5% to 40% B for 4.5 minutes, then 40% for 2.5 minutes, followed by 5% B for 1 minute. Flow rate: 2.8 mL / min, Column temperature: 40°C, 98% de. The compound structure was confirmed using X-rays. Example 9: Synthesis of U6410 [ka] overview: [ka]

[0409] The synthesis of U6461 can be found in Example 11 of this specification.

[0410] Synthesis of U6410 [ka] To a solution of U6461 (300 mg, 0.696 mmol) in MeOH (50 mL), Pd(OH)2 (600 mg, dry) was added. The mixture was stirred at 50 Psi and 50 °C for 48 hours. The mixture was filtered, concentrated, and purified by combiflush (0-50% alkylethanol in PE) to obtain U6410 (35 mg, 12%) as a solid. 1H NMR(400MHz,CDCl3)δ 2.39-2.29(m,2H),2.26-2.15(m,1H),2.03-1.87(m,3H),1.70-1.56(m,5H),1.53-1.37(m,8H),1.36- 1.24(m,4H),1.23-1.16(m,7H),1.15-1.04(m,7H),1.02-0.90(m,5H),0.89-0.83(m,3H),0.65(s,3H). LCMS-Rt=1.029min (2.0 minutes of chromatography), 30-90AB_E, 100% purity, C 28 H 47 O2[M+H-H2O] + The MS ESI calculated value is 415, and the measured value is also 415. Example 10: Synthesis of U6408 and U6409 [ka] overview: [ka]

[0411] The synthesis of U6461 can be found in Example 11 of this specification.

[0412] 1101 synthesis [ka] To a suspension of bromo(methyl)triphenylphosphoran (1.24 g, 3.48 mmol) in THF (45 mL), t-BuOK (389 mg, 3.48 mmol) was added. The mixture was stirred at 50°C for 30 minutes under N2. Then, a solution of U6461 (300 mg, 0.696 mmol) in THF (5 mL) was added, and the mixture was stirred at 50°C for 1 hour. The mixture was quenched with saturated NH4Cl (50 mL) and extracted with RINKAN (3 × 15 mL). The combined organic phase was dried over Na2SO4, filtered, concentrated, and purified by combiflush (0-30% RINKAN in PE) to obtain the desired product (72 mg, 24%) as a solid. 1 H NMR(400MHz,CDCl3)δ 5.80-5.75(m,1H),4.93(s,1H),4.73(s,1H),2.43-2.36(m,1H),2.20-2.01(m,4H),1.99-1.86(m,1H),1.80-1.62(m,3H),1.61-1.58( m,2H),1.56-1.46(m,1H),1.45-1.22(m,9H),1.21-1.18(m,7H),1.16-1.05(m,8H),0.99-0.91(m,3H),0.88-0.82(m,3H),0.71(s,3H).

[0413] Synthesis of 1102 [ka] To a solution of 1101 (72 mg, 0.167 mmol) in THF (5 mL), Pd / C (wet, 150 mg) was added. The mixture was stirred at 15 Psi, 15 °C for 12 hours. The mixture was filtered, concentrated, and purified by combiflush (0-10% ethyl acetate in PE) to obtain impure 1102 (50 mg, 69%) as a solid.

[0414] Combination of U6408 and U6409 [ka] 50 mg of impure 1102 was separated by SFC (column: AD (250 mm × 30 mm, 10 μm), gradient: 30-30% B (A = 0.05% NH3 / H2O, B = MeOH), flow rate: 60 mL / min) to obtain U6408 (peak 1, 5 mg, 10%) and U6409 (peak 2, 7 mg, 14%) as solids. Based on the characteristic HNMR of compounds 82 and U6429, a) 7-α-H isomer with a singleline H-6 at high magnetic field; b) 7-β-H isomer with a doubleline H-6 at low magnetic field, the stereochemistry at C7 was assigned. U6408 1H NMR(400MHz,CDCl3)δ 5.33-5.28(m,1H),2.43-2.34(m,1H),2.05-1.94(m,3H),1.91-1.80(m,1H),1.77-1.67(m,2H),1.65-1.61(m,2H),1.52-1.4 2(m,6H),1.38-1.23(m,6H),1.19(s,6H),1.15-1.07(m,6H),1.03(s,3H),0.98-0.91(m,4H),0.87-0.79(m,6H),0.67(s,3H). LCMS Rt=1.245min (2.0 minutes of chromatography), 30-90AB_E, 100% purity, C 29 H 47 [M+H-2H2O] + The MS ESI calculated value is 395, and the measured value is also 395. SFC Rt = 4.245 min (10-minute chromatography), Column: ChiralPak AD-3 150 × 4.6 mm ID, 3 μm, Mobile phase: A: CO2 B: Ethanol (0.05% DEA), Gradient: 5% to 40% B for 5.5 minutes, then 40% B held for 3 minutes, followed by 5% B for 1.5 minutes, Flow rate: 2.5 mL / min, Column temperature :40℃, 100% de. U6409 1 H NMR(400MHz,CDCl3)δ 5.04-4.99(m,1H),2.38-2.28(m,1H),2.07-1.96(m,2H),1.92-1.78(m,2H),1.72-1.62(m,4H),1.53-1.44(m ,4H),1.43-1.25(m,8H),1.19(s,6H),1.16-1.05(m,6H),0.99-0.91(m,10H),0.88-0.81(m,3H),0.68(s,3H). LCMS Rt=1.253min (2.0 minutes of chromatography), 30-90AB_E, 100% purity, C 29 H 47 [M+H-2H2O] + The MS ESI calculated value is 395, and the measured value is also 395. SFC Rt = 4.967 min (10-minute chromatography), Column: ChiralPak AD-3 150 × 4.6 mm ID, 3 μm, Mobile phase: A: CO2, B: Ethanol (0.05% DEA), Gradient: 5% to 40% B for 5.5 minutes, then 40% B held for 3 minutes, followed by 5% B for 1.5 minutes, Flow rate: 2.5 mL / min, Column temperature: 40°C, 100% DEA. Example 11: Synthesis of U6461, U6429, and U6479 [ka] overview: [ka]

[0415] The synthesis of 1201 can be found in Example 4 of this specification.

[0416] 1202 synthesis [ka] To a solution of impure 1201 (14.9 g, 35.7 mmol) in THF (600 mL), MeLi (111 mL, 178 mmol, 1.6 M in ether) was added dropwise at 0°C. After stirring at 15°C for 30 minutes, the mixture was quenched with saturated NH4Cl (500 mL) and extracted with siRNA (3 × 200 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated to obtain a crude residue, which was ground with MeCN (300 mL) to obtain 11 g of crude product as a solid. The crude product was recrystallized from siRNA (300 mL) to obtain 1202 (9 g, purity 80%, 49%) as a solid. 1H NMR 1202(400MHz,CDCl3)δ 5.28-5.25(m,1H),2.40-2.32(m,1H),2.05-1.92(m,3H),1.90-1.80(m,1H),1.79-1.58(m,3H),1.56-1.51(m,5H),1.50-1.39(m,7H),1.3 8-1.28(m,2H),1.27-1.16(m,6H),1.15-1.04(m,5H),1.02(s,3H),1.00-0.96(m,1H),0.95-0.88(m,4H),0.87-0.77(m,3H),0.68(s,3H).

[0417] Synthesis of U6461 [ka] To a solution of 1202 (5 g, 11.9 mmol) in ethyl acetate (300 mL), molecular sieves (10 g) and t-butyl hydroperoxide (11.9 mL, 71.4 mmol, 6 M in decane) were added. The suspension was stirred under a nitrogen atmosphere for 30 minutes, and then manganese(III) acetate dihydrate (956 mg, 3.57 mmol) was added all at once. The reaction mixture was stirred at 15°C for 48 hours. The solid was filtered off. The filtrate was washed with Na₂SO₃ (200 mL) and brine (200 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0-15% siRNA in DCM) to obtain impure U6461 (2 g, 40%) as a solid. 100 mg of this solid was recrystallized in MeCN (30 mL) at 90°C to obtain pure U6461 (34 mg, 34%) as a solid. 1H NMR(400MHz,CDCl3)δ 5.67-5.64(m,1H),2.58-2.49(m,1H),2.47-2.36(m,1H),2.31-2.20(m,2H),2.06-1.81(m,3H),1.79-1.68(m,2H),1.55-1.49(m,3H) ),1.48-1.37(m,5H),1.36-1.24(m,5H),1.23-1.16(m,11H),1.15-1.05(m,3H),0.92-0.92(m,3H),0.90-0.83(m,3H),0.68(s,3H). LCMS Rt=1.059min (2.0 minutes of chromatography), 30-90 AB, 100% purity, C 28 H 47 O3[M+H] + The MS ESI calculated value is 431, and the measured value is also 431.

[0418] Synthesis of U6429 [ka] To a solution of U6461 (500 mg, 1.16 mmol) in MeOH (30 mL), CeCl3 (857 mg, 3.48 mmol) was added. After stirring at 15°C for 30 minutes, NaBH4 (197 mg, 5.80 mmol) was added gradually. The reaction mixture was stirred at 15°C for 30 minutes. The mixture was quenched with saturated NH4Cl (50 mL) and extracted with  (3 × 30 mL). The combined organic phase was washed with brine (2 × 100 mL), dried over Na2SO4, filtered, and concentrated to obtain 470 mg of crude product, which was recrystallized from MeCN (100 mL) to obtain U6429 (370 mg, 74%) as a solid. Based on a) the 7-α-H isomer having a singleline H-6 under high magnetic field conditions; and b) the 7-β-H isomer having a doubleline H-6 under low magnetic field conditions, the stereochemistry at C7 was assigned in comparison to compound 82, according to the literature (Synthesis, 1987, 1002). 1H NMR(400MHz,CDCl3)δ 5.25-5.22(m,1H),3.89-3.82(m,1H),2.43-2.35(m,1H),2.13-1.97(m,2H),1.96-1.77(m,2H),1.76-1.60(m,3H),1.53- 1.40(m,8H),1.39-1.28(m,5H),1.24-1.18(m,7H),1.16-0.99(m,9H),0.97-0.91(m,3H),0.88-0.82(m,3H),0.69(s,3H). LCMS Rt=0.999min (2.0 minutes of chromatography), 30-90AB_E, 100% purity, C 28 H 45 O[M+H-2H2O] + The MS ESI calculated value was 397, and the measured value was 397. The compound structure was confirmed by X-ray.

[0419] Synthesis of U6479 [ka] To a solution of U6429 (100 mg, 0.231 mmol) in MeOH (30 mL), Pd(OH)2 (200 mg, dry) was added. The mixture was stirred at 50°C for 48 hours under H2 (50 Psi). The mixture was filtered, concentrated, and purified by combiflush (0-50% siRNA in PE) to obtain U6479 (23 mg, 23%) as a solid. 1 H NMR(400MHz,CDCl3)δ 3.44-3.29(m,1H),2.03-1.95(m,1H),1.94-1.76(m,2H),1.67-1.58(m,4H),1.53-1.42(m,6H),1.42-1.33(m,5H), 1.32-1.24(m,4H),1.23-1.11(m,11H),1.10-1.04(m,2H),0.97-0.91(m,4H),0.90-0.82(m,6H),0.75-0.63(m,4H). LCMS Rt=1.010min (2.0 minutes of chromatography), 30-90AB_E, 100% purity, C 28 H 45 [M+H-3H2O]+ The MS ESI calculated value is 381, and the measured value is also 381. Example 12: EC 50 and E Max data Automatic Patch-Clamping System (QPatch HTX)

[0420] In this study, the GRIN1 / 2A subtype glutamate activation channel was found to be stable. Transfected HEK 293 cells were used with submaximal NMDA concentrations (300 μM NMDA, administered concurrently with 8 μM glycine) to investigate the negative allosteric modulation of the test compound. cell culture Generally, cells are subcultured at approximately 80%–90% confluence. For electrophysiological measurements, cells are collected from sterile culture flasks containing complete culture medium at approximately 80%–90% confluence. The cells are then transferred as a suspension in PBS to a QPatch 16X or QPatch HTX system and centrifugated / washed. Standard laboratory conditions: Incubate cells at 37°C in a humidified atmosphere containing 5% CO2 (approximately 95% relative humidity). Cells were continuously maintained and subcultured in a sterile culture flask containing a 1:1 mixture of Dulbecco's modified Eagle medium supplemented with 10% fetal bovine serum, 1% penicillin / streptomycin solution, and 50 μM AP-5 blocker, and nutrient mixture F-12 (D-MEM / F-12 1×, liquid, containing L-glutamine). Antibiotics: Supplement the complete medium described above with 100 μg / mL hygromycin, 15 μg / mL blastosidine, and 1 μg / mL puromycin. Induction of expression: Add 2.5 μg / mL tetracycline 24 hours before the start of the experiment. Administration Formulation The dose level is converted to the test compound as supplied. A vehicle is added to achieve a stock concentration of 10 mM (store at -10°C to -30°C). A further 1.0 mM stock solution is prepared in DMSO. Details of stock solution use (thawing, dosage formulation) are recorded in the raw data. The time of stock solution use is detailed in the report. Test compound concentration The dose level is converted to the test compound as supplied. A vehicle is added to achieve a stock concentration of 10 mM (store at -10°C to -30°C). A further 1.0 mM stock solution is prepared in DMSO. Details of stock solution use (thawing, dosage formulation) are recorded in the raw data. The time of stock solution use is detailed in the report. A single test concentration of 1.0 μM is tested. Immediately before the electrophysiological experiment, prepare all test solutions by diluting the stock solution with either a magnesium-free bath solution alone or a magnesium-free bath solution containing NMDA (300 μM) and glycine (8.0 μM), and keep them at room temperature (19°C to 30°C) when ready for use. Use 0.1% DMSO as the vehicle. Preparation frequency: A fresh solution of the test compound is prepared daily for each test concentration. Stability of administered formulation: Record all preparation times in the raw data. Record any observations regarding the instability of the test compound in the raw data. Storage of the administered preparation: On the day of the experiment, keep the administered preparation at room temperature (19°C to 30°C) when ready to use. Bath solution For experimental preparation and giga-ohm seal formation, use the following standard bath solutions: Sodium chloride: 137 mM; Potassium chloride: 4 mM; Calcium chloride: 1.8 mM; Magnesium chloride: 1 mM; HEPES: 10 mM; D-glucose: 10 mM; Cremophor: 0.02%; pH (NaOH): 7.4 Prepare a 1x bath solution by diluting a glucose-free 10x bath solution and a 100x glucose solution with water at least every 7 days. Both stock solutions were prepared before the start of the experiments in this study and stored at 1°C to 9°C (10x bath solution) or -10°C to -30°C (100x glucose solution). Record the batch number of the bath solution used in the experiment in the raw data. When in use, keep the 1x bath solution at room temperature (19°C to 30°C). When not in use, store the 1x bath solution at 1°C to 9°C. After giga-seal formation, use the following Mg-free bath solution: Sodium chloride: 137 mM; Potassium chloride: 4 mM; Calcium chloride: 2.8 mM; HEPES: 10 mM; D-glucose: 10 mM; Cremophor: 0.02%; pH (NaOH): 7.4 Prepare this Mg-free bath solution as a 1× solution and store it at 1°C to 9°C. Prepare a fresh solution at least every 10 days. intracellular solution From the frozen 1× intracellular solution prepared before the start of this study, the 1× intracellular solution is thawed daily, aliquoted, and stored at -10°C to -30°C. When in use, the 1× intracellular solution is kept at room temperature (19°C to 30°C). The remaining 1× intracellular solution is stored in the refrigerator (1°C to 9°C). The 1× intracellular solution contains the components outlined below: Potassium chloride: 130 mM; Magnesium chloride: 1 mM; Mg-ATP: 5 mM; HEPES: 10 mM; EGTA: 5 mM; pH (KOH): 7.2 Cell processing In this study, cells were sequentially perfused with NMDA / glycine, the test compound, or the test compound / NMDA / glycine. In all cases, a pre-washing step with the test compound for at least 30 seconds should be performed between applications. See Table A below for details. Each experimental type will be analyzed in at least n=3 isolated cells. Before the start of the experiments in this study, NMDA and glycine stock solutions will be prepared and frozen until the day of the experiment (-10°C to -30°C). Immediately before the electrophysiological experiments, the frozen stock solutions will be thawed and diluted. Control: To ensure successful NMDA receptor expression, the effects of vehicle (0.1% DMSO) and D-(-)-2-amino-5-phosphonopentanoic acid (AP-5) (100 μM) were measured every two weeks in three cell lines. Before the start of the experiments in this study, a 50 mM stock solution of AP-5 was prepared, aliquoted, and frozen until the day of the experiment (-10°C to -30°C). Immediately before the electrophysiological experiments, the frozen stock solution was thawed and then diluted with a magnesium-free bath solution containing NMDA (300 μM) and glycine (8.0 μM) to obtain a final perfusion concentration of 100 μM. Experimental Procedure Transfer the cells as a suspension in serum-free medium to the QPatch HTX system and maintain them in a cell storage tank / stirrer during the experiment. Maintain all solutions applied to the cells, including intracellular solutions, at room temperature (19°C–30°C). During the sealing process, use the standard bath solution described above. Maintain all solutions applied to the cells, including the pipette solution, at room temperature (19°C to 30°C). After the formation of a gigaohm seal between the patch electrode and individual transfected HEK293 cells, perfuse only with the Mg-free bath solution and rupture the cell membrane to ensure electrical access to the inside of the cell (whole-cell patch configuration). Apply 300 μM NMDA (and 8.0 μM glycine) to the patch-clamped cells for 5 seconds and measure the inward current. Throughout the entire experiment, the cells are voltage-clamped to a holding potential of -80 mV.

[0421] In the analysis of the test compounds, NMDA receptors are stimulated with 300 μM NMDA, 8.0 μM glycine, and the test compounds listed below. A 30-second pre-wash step with the test compounds is performed between applications. [Table A] [Table B]

[0422] The results are reported in Table 1. Table 1-1 Table 1-2 Table 1-3

[0423] abbreviation PCC: Pyridinium chlorochromate; t-BuOK: Potassium tert-butoxide; 9-BBN: 9-Borabicyclo[3.3.1]nonane; Pd(t-Bu3P)2: Bis(tri-tert-butylphosphine)palladium(0); AcCl: Acetyl chloride; i-PrMgCl: Isopropyl magnesium chloride; TBSCl: Tert-butyl(chloro)dimethylsilane; (i-PrO)4Ti: Titanium tetraisopropoxide; BHT: 2,6-di-t-butyl-4-methylphenoxide; Me: Methyl; i-Pr: Isopropyl; t-Bu: Tert-butyl; Ph: Phenyl; Et: Ethyl; Bz: Benzoyl; BzCl: Benzoyl chloride; CsF: Cesium fluoride; DCC: Dicyclohexylcarbodiimide; DCM: Dichloromethane; DMAP: 4-Dimethylaminopyridine; DMP: Des-Martinperiodinane; EtMgBr: Ethylmagnesium bromide; Â: Ethyl acetate; TEA: Triethylamine; AlaOH: Alanine; Boc: t-Butoxycarbonyl. Py: Pyridine; TBAF: Tetra-n-butylammonium fluoride; THF: Tetrahydrofuran; TBS: t-butyldimethylsilyl; TMS: Trimethylsilyl; TMSCF3: (Trifluoromethyl)trimethylsilane; Ts: p-toluenesulfonyl; Bu: Butyl; Ti(OiPr)4: Tetraisopropoxytitanium; LAH: Lithium aluminum hydride; LDA: Lithium diisopropylamide; LiOH.H2O: Lithium hydroxide hydrate; MAD: Methylaluminum bis(2,6-di-t-butyl-4-methylphenoxide); MeCN: Acetonitrile; NBS: N-bromosuccinimide; Na2SO4: Sodium sulfate; Na2S2O3: Sodium thiosulfate; PE: Petroleum ether; MeCN: Acetonitrile; MeOH: Methanol; Boc: t-butoxycarbonyl; MTBE: Methyl tert-butyl ether; K-Selectlide: Potassium tri(s-butyl)boron hydride Other Embodiments

[0424] In a claim, articles (e.g., "a," "an," and "the") may mean one or more unless otherwise indicated or evident from the context. Unless otherwise indicated or evident from the context, a claim or description containing "or" between one or more members of a group is considered to satisfy that one, more than one, or all members of the group are present in, used in, or otherwise related to a given product or process. The present invention assumes that exactly one member of the group is present in, used in, or related to a given product or process. This includes embodiments that are otherwise related. The present invention includes embodiments in which one or more or all of the group members are present in, used in, or otherwise related to a given product or process.

[0425] Furthermore, the present invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims are introduced in another claim. For example, any claim dependent on another claim may be modified to include one or more limitations found in any other claim dependent on the same basic claim. Where elements are presented as a list, for example in the form of a Markush group, each subgroup of that element is also disclosed, and any element may be removed from that group. In general, where the present invention or an aspect of the present invention is referred to as including certain elements and / or features, it should be understood that certain embodiments of the present invention or an aspect of the present invention consist of or essentially consist of such elements and / or features. For the sake of simplicity, those embodiments are not explicitly shown herein in these terms. Note that the terms “comprising” and “containing” are intended to be open and may also include further elements or steps. Where a scope is given, the endpoint is included. Furthermore, unless otherwise indicated or evident from the context and the understanding of those skilled in the art, values ​​expressed as ranges may, unless the context clearly indicates otherwise, assume any specific value or subrange within the ranges described in the various embodiments of the present invention up to one-tenth of the lower limit unit of that range.

[0426] This application refers to various issued patents, published patent applications, academic articles, and other publications (all of which are incorporated herein by reference). In the event of any conflict between any reference incorporated herein and this specification, this specification shall prevail. Furthermore, any particular embodiment of the Invention that falls within the scope of the Prior Art may be expressly excluded from any one or more of the claims. Such embodiments are considered to be known to those skilled in the art and may be excluded even if such exclusion is not expressly indicated herein. Any particular embodiment of the Invention may be excluded from any claim for any reason, whether or not it relates to the existence of the Prior Art.

[0427] Those skilled in the art can identify or verify 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 is as set forth in the appended claims. Those skilled in the art will recognize that various changes and modifications to this description can be made without departing from the spirit or scope of the invention as defined in the following claims.

[0428] According to a preferred embodiment of the present invention, for example, the following is provided: (Section 1) Formula (A): [ka] [In the formula, R 1A and R 1B Each of them independently is hydrogen, a substituted or unsubstituted alkyl, a carbocykryl, a heterocyclyl, an aryl or heteroaryl, or R 1A and R 1B They form a 3- to 8-membered ring together with the carbon atoms to which they are bonded; n is either 1 or 2; R 2A and R 2B Each of these is independently hydrogen, halo, -OR C , alkyl, alkenyl, alkynyl, aryl or heteroaryl, where R C is either hydrogen or alkyl, or R 2A and R 2B They form an oxo group together with the carbon atoms to which they are bonded, and here, R 2A and R 2B Both are not hydrogen at the same time; R 3 This includes hydrogen, alkyl, alkenyl, alkynyl or -OR A And here, R A It is alkyl; R 4It does not exist, or it is hydrogen; and [ka] represents a single bond or a double bond, where, [ka] If one of them is a double bond, the other [ka] It is a single bond; [ka] If both are single bonds, R 4 is hydrogen; and [ka] If one of them is a double bond, R 4 [The compound or a pharmaceutically acceptable salt of the compound does not exist.] (Section 2) The compound described in item 1 above, wherein n is 1. (Section 3) The compound described in item 1 above, wherein n is 2. (Section 4) R 1A , R 3 and R 4 is hydrogen, and R 1B If R is an unsubstituted isopropyl, 2A and R 2B They do not form an oxo group with the carbon atoms to which they are bonded; and R 4 R does not exist, 3 is hydrogen, and R 1A and R 1B If R is -CH3, 2A It is not -CH3, and R 2B The compound described in item 1 above, which is not -OH. (Item 5) R 4 R does not exist, 2A is -OH, and R2B is hydrogen or -CF3, and R 1A and R 1B If R is -CH3, 3 It is not hydrogen; and R 1A and R 1B is -CH3, and R 3 If R is hydrogen, 2A and R 2B The compound described in item 1 above, wherein they do not form an oxo group together with the carbon atoms to which they are bonded. (Section 6) The compound of formula (A) is of formula (AI): [ka] The compound described in item 1 above, which is a compound of the above. (Section 7) The compound of formula (A) is of formula (A-II): [ka] The compound described in item 1 above, which is a compound of the above. (Section 8) The compound of formula (A) is of formula (A-III): [ka] The compound described in item 1 above, which is a compound of the above. (Section 9) The compounds of formula (A) are formulas (A-IV), (AV), or (A-VI): [ka] [ka] [In the formula, R 2C is hydrogen or alkyl, and R 3 is alkyl, alkenyl, alkynyl or -OR A And here, R A The compound described in item 1 above, which is an alkyl compound. (Section 10) The compounds of formula (A) are those of formulas (A-VII), (A-VIII), or (A-IX): [ka] [In the formula, R 3 is alkyl, alkenyl, alkynyl or -OR A And here, R A The compound described in item 1 above, which is an alkyl compound. (Section 11) The compound of formula (A) is of formula (AX): [ka] [In the formula, R 3 is alkyl, alkenyl, alkynyl or -OR A And here, R A The compound described in item 1 above, which is an alkyl compound. (Section 12) The compound of formula (A) is of formula (A-XII) [ka] [In the formula, R' is alkyl or -OR A And here, R A The compound described in item 1 above, wherein p is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, or 3. (Section 13) R 4 It does not exist, R 2A and R 2B One of them is -OH, and R 3 A compound that is not hydrogen, as described in any one of items 1 to 12 above. (Section 14) R 1A and R 1B Each of the compounds is independently an unsubstituted or substituted alkyl group, as described in any one of items 1 to 11 above. (Section 15) R 1Aand R 1B Each of the compounds is independently selected from the group consisting of haloalkyl, alkoxyalkyl, -CH3, -CH2CH3, -CH(CH3)2, -CF3, and -CH2OCH3, as described in item 14 above. (Section 16) R 1A and R 1B Each of the compounds is independently a substituted alkyl group, as described in any one of items 1 to 11 above. (Section 17) R 1A and R 1B The compound described in item 16 above, wherein each of the members is independently a haloalkyl. (Section 18) R 1A The compound is one of the compounds described in any one of items 1 to 11 above, wherein the compound is -CF3 or -CH2OCH3. (Section 19) R 1A and R 1B The compound described in any one of items 1 to 11 above, wherein is an unsubstituted or substituted alkyl group. (Section 20) R 1A and R 1B A compound described in any one of items 1 to 11 above, wherein the compound is -CH3. (Item 21) R 1A and R 1B The compound described in any one of items 1 to 11 above, wherein they form a 3- to 8-membered ring together with the carbon atoms to which they are bonded. (Section 22) R 1A is hydrogen, and R 1B The compound is an alkyl, carbocyryl, heterocyclyl, aryl, or heteroaryl compound as described in any one of items 1 to 11 above. (Section 23) R 1A is a substituted alkyl or unsubstituted C2-C6 alkyl, and R 1B The compound is a substituted or unsubstituted C1-C6 alkyl group, as described in any one of items 1 to 11 above. (Section 24) R 2Aand R 2B Each of the compounds is independently a substituted or unsubstituted alkyl group, as described in any one of items 1 to 8 or 13 above. (Section 25) R 2A and R 2B Each of the compounds is independently -F, as described in any one of items 1 to 8 or 12 above. (Section 26) R 2A and R 2B is -CH3, and R 3 is alkyl, alkenyl, alkynyl or -OR A And here, R A A compound according to any one of items 1 to 8 or 12 above, wherein is an alkyl group. (Section 27) R 3 This includes substituted or unsubstituted alkyl, alkenyl, alkynyl, or -OR A And here, R A The compound is an alkyl compound as described in any one of items 1 to 12 above. (Section 28) R 3 The compound described in any one of items 1 to 12 above, wherein is a substituted or unsubstituted alkyl group. (Section 29) R 2A and R 2B Each of them is independently hydrogen, and R 3 The compound described in any one of items 1 to 8 or 12 above, wherein is a substituted or unsubstituted alkyl group. (Section 30) A pharmaceutical composition comprising the compound described in item 1 above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. (Section 31) A method for inducing sedation or anesthesia, comprising the step of administering to a subject an effective amount of the compound described in item 1 above or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition thereof. (Section 32) A method for treating or preventing any of the disorders described herein, comprising the step of administering an effective amount of the compound described in item 1 above or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition thereof to a subject in need of such treatment or prevention. (Section 33) The method according to item 32 above, wherein the disorder is a gastrointestinal (GI) disorder, constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, structural disorders affecting the GI, anal disorders, hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas, colon polyps, cancer, or colitis. (Section 34) The method described in item 32 above, wherein the disorder is inflammatory bowel disease. (Section 35) The method according to paragraph 32, wherein the disorder is cancer, diabetes, or sterol synthesis disorder. (paragraph 36) The method described in item 32 above, wherein the disorder is a metabolic disorder. (Section 37) The method described in item 32 above, wherein the disorder is an autoimmune disorder. (Section 38) The method according to item 32, wherein the aforementioned disorders are rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and psoriasis vulgaris. (Section 39) A method for treating or preventing a CNS-related condition, comprising the step of administering an effective amount of the compound described in item 1 above or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition thereof to a subject in need of such treatment or prevention. (Section 40) The aforementioned CNS-related conditions include adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, and social phobia), cognitive impairments (including Alzheimer's disease and other forms of dementia), dissociative disorders, eating disorders, mood disorders (including depression and postpartum depression, bipolar disorder, dysthymic disorder, and suicidal tendencies), schizophrenia or other psychotic disorders (including schizoaffective psychosis), sleep disorders (including insomnia), substance-related disorders, personality disorders (including obsessive-compulsive personality disorder), and autism spectrum disorders (including mutations in Shank group proteins (Shank3)). The method according to item 39 above, which includes, but is not limited to, a neurodevelopmental disorder (such as Rett syndrome and tuberous sclerosis complex), multiple sclerosis, sterol synthesis disorder, pain (such as acute and chronic pain), secondary brain injury to a certain medical condition (such as hepatic encephalopathy and anti-NMDA receptor encephalitis), paroxysmal disorder (such as status epilepticus and monogenic epilepsy, e.g., Dravet disease), stroke, traumatic brain injury, motor impairment (such as Huntington's disease and Parkinson's disease), visual impairment, hearing impairment, or tinnitus. (Section 41) The method according to item 32 above, wherein the impairment is a sterol synthesis disorder. (Section 42) Formula (B): [ka] [In the formula, R 1A and R 1B Each of them independently is hydrogen, a substituted or unsubstituted alkyl, a carbocykryl, a heterocyclyl, an aryl or heteroaryl, or R 1A and R 1B They form a 3- to 8-membered ring together with the carbon atoms to which they are bonded; n is either 1 or 2; R 2A and R 2B Each of these is independently hydrogen, halo, -OR C , alkyl, alkenyl, alkynyl, aryl or heteroaryl, where R Cis either hydrogen or alkyl, or R 2A and R 2B They form an oxo group together with the carbon atoms to which they are bonded, and here, R 2A and R 2B Both are not hydrogen at the same time; R 3 is alkyl, alkenyl, alkynyl or -OR A And here, R A It is alkyl; R 4 It does not exist, or it is hydrogen; and [ka] represents a single bond or a double bond, where, [ka] If one of them is a double bond, the other [ka] It is a single bond; [ka] If both are single bonds, R 4 is hydrogen; and [ka] If one of them is a double bond, R 4 [The compound or a pharmaceutically acceptable salt of the compound does not exist.] (Section 43) The compound described in item 42 above, wherein n is 1. (Section 44) The compound described in item 42 above, wherein n is 2. (Section 45) The compound of formula (B) is of formula (BI): [ka] The compound described in item 42 above, which is a compound of the above. (Section 46) The compound of formula (B) is of formula (B-II): [ka] The compound described in item 42 above, which is a compound of the above. (Section 47) The compound of formula (B) is of formula (B-III): [ka] The compound described in item 42 above, which is a compound of the above. (Section 48) The compound of formula (B) is of formula (B-IV), (BV), or (B-VI): [ka] [In the formula, R 2C is hydrogen or alkyl, and R 3 Alkyl, alkenyl, Alkinyl or -OR A And here, R A The compound described in item 42 above, which is an alkyl compound. (Section 49) The compounds of formula (B) are of formulas (B-VII), (B-VIII), or (B-IX): [ka] [In the formula, R 3 is alkyl, alkenyl, alkynyl or -OR A And here, R A The compound described in item 42 above, which is an alkyl compound. (Section 50) The compound of formula (B) is of formula (BX): [ka] [In the formula, R 3 is alkyl, alkenyl, alkynyl or -OR A And here, R AThe compound described in item 42 above, which is an alkyl compound. (Section 51) The compound of formula (B) is of formula (B-XII) [ka] [In the formula, R' is alkyl or -OR A And here, R A The compound described in item 42 above, which is a compound of [where is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, or 3]. (Section 52) R 1A and R 1B Each of the compounds is independently an unsubstituted or substituted alkyl group, as described in any one of items 42 to 50 above. (Section 53) R 1A and R 1B Each of the compounds is independently selected from the group consisting of haloalkyl, alkoxyalkyl, -CH3, -CH2CH3, -CH(CH3)2, -CF3, and -CH2OCH3, as described in item 52 above. (Section 54) R 1A and R 1B Each of the compounds is independently a substituted alkyl group, as described in any one of items 42 to 50 above. (Section 55) R 1A and R 1B Each of the compounds is independently a haloalkyl, as described in any one of items 42 to 50 above. (Section 56) R 1A The compound is one of the compounds described in any one of items 42 to 50 above, wherein the compound is -CF3 or -CH2OCH3. (Section 57) R 1A and R 1B A compound described in any one of items 42 to 50 above, wherein is -CH3. (Section 58) R 1A and R 1BThe compound described in any one of items 42 to 50 above, wherein they form a 3- to 8-membered ring together with the carbon atoms to which they are bonded. (Section 59) R 1A is hydrogen, and R 1B The compound is one of the compounds described in any one of items 42 to 50 above, wherein is an alkyl, carbocyryl, heterocyclyl, aryl, or heteroaryl. (Section 60) R 1A is a substituted alkyl or unsubstituted C2-C6 alkyl, and R 1B The compound is a substituted or unsubstituted C1-C6 alkyl group, as described in any one of items 42 to 50 above. (Section 61) R 2A and R 2B Each of the compounds is independently a substituted or unsubstituted alkyl group, as described in any one of items 42 to 50 above. (Section 62) R 2A and R 2B Each of the compounds is independently -F, as described in any one of items 42 to 51 above. (Section 63) R 2A and R 2B is -CH3, and R 3 is alkyl, alkenyl, alkynyl or -OR A And here, R A A compound according to any one of items 42 to 51 above, wherein is an alkyl group. (Section 64) R 3 This includes substituted or unsubstituted alkyl, alkenyl, alkynyl, or -OR A And here, R A A compound according to any one of items 42 to 51 above, wherein is an alkyl group. (Section 65) R 3 The compound according to any one of items 42 to 51 above, wherein is a substituted or unsubstituted alkyl group. (Section 66) R 2A and R 2BEach of them is independently hydrogen, and R 3 The compound according to any one of items 42 to 51 above, wherein is a substituted or unsubstituted alkyl group. (Section 67) A pharmaceutical composition comprising the compound described in item 42 above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. (Section 68) A method for inducing sedation or anesthesia, comprising the step of administering to a subject an effective amount of the compound described in item 42 above or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition thereof. (Section 69) A method for treating or preventing any of the disorders described herein, comprising the step of administering an effective amount of the compound described in item 42 above or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition thereof to a subject in need of such treatment or prevention. (Section 70) The method according to item 69 above, wherein the disorder is a gastrointestinal (GI) disorder, constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, structural disorders affecting the GI, anal disorders, hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas, colon polyps, cancer, or colitis. (Section 71) The method according to item 69 above, wherein the disorder is inflammatory bowel disease. (Section 72) The method according to item 69, wherein the disorder is cancer, diabetes, or sterol synthesis disorder. (Section 73) The method described in paragraph 69 above, wherein the disorder is a metabolic disorder. (Section 74) The method described in paragraph 69 above, wherein the disorder is an autoimmune disorder. (Section 75) The method according to item 69, wherein the aforementioned disorders are rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and psoriasis vulgaris. (Section 76) A method for treating or preventing a CNS-related condition, comprising the step of administering an effective amount of the compound described in item 42 above or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition thereof to a subject in need of such treatment or prevention. (Section 77) The aforementioned CNS-related conditions include adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, and social phobia), cognitive impairments (including Alzheimer's disease and other forms of dementia), dissociative disorders, eating disorders, mood disorders (including depression and postpartum depression, bipolar disorder, dysthymic disorder, and suicidal tendencies), schizophrenia or other psychotic disorders (including schizoaffective psychosis), sleep disorders (including insomnia), substance-related disorders, personality disorders (including obsessive-compulsive personality disorder), and autism spectrum disorders (including mutations in Shank group proteins (Shank3)). The method according to item 76 above, which includes, but is not limited to, a neurodevelopmental disorder (such as Rett syndrome and tuberous sclerosis complex), multiple sclerosis, sterol synthesis disorder, pain (such as acute and chronic pain), secondary brain injury to a certain medical condition (such as hepatic encephalopathy and anti-NMDA receptor encephalitis), paroxysmal disorder (such as status epilepticus and monogenic epilepsy, e.g., Dravet disease), stroke, traumatic brain injury, motor impairment (such as Huntington's disease and Parkinson's disease), visual impairment, hearing impairment, or tinnitus. (Section 78) The method according to item 69 above, wherein the impairment is impaired sterol synthesis. (Section 79) Equation (I): [ka] [In the formula, R 1A and R 1B Each of them independently is hydrogen, a substituted or unsubstituted alkyl, a carbocyacrylic, a heterocycline, an aryl or heteroaryl, or R 1A and R 1B They form a 3- to 8-membered ring together with the carbon atoms to which they are bonded; R 2A and R 2B Each of these is independently hydrogen, halo, -OR C , alkyl, alkenyl, alkynyl, aryl or heteroaryl, where R C is either hydrogen or alkyl, or R 2A and R 2B They form an oxo group together with the carbon atoms to which they are bonded, and here, R 2A and R 2B Both are not hydrogen at the same time; R 3 This includes hydrogen, alkyl, alkenyl, alkynyl or -OR A And here, R A It is alkyl; R 4 It does not exist, or it is hydrogen; and [ka] represents a single bond or a double bond, where, [ka] If one of them is a double bond, the other [ka] It is a single bond; [ka] If both are single bonds, R 4 is hydrogen; and [ka] If one of them is a double bond, R 4 It does not exist; However, R 1A , R 3 and R 4 is hydrogen, and R 1B If R is an unsubstituted isopropyl, 2A and R2B They do not form an oxo group with the carbon atoms to which they are bonded; and R 4 R does not exist, 3 is hydrogen, and R 1A and R 1B If R is -CH3, 2A It is not -CH3, and R 2B Compounds of which are not -OH, or their pharmaceutically acceptable salts. (Section 80) R 1A , R 3 and R 4 is hydrogen, R 1B It is unsubstituted isopropyl, and R 2A and R 2B The compounds described in item 79 above, wherein they do not form an oxo group together with the carbon atoms to which they are bonded. (Section 81) R 4 It does not exist, R 3 is hydrogen, R 1A and R 1B is -CH3, R 2A It is not -CH3, and R 2B The compound described in item 79 above, which is not an -OH group. (Section 82) The compound of formula (I) is of formula (IA): [ka] The compound described in item 79 above, which is a compound of the above. (Section 83) The compound of formula (I) is of formula (IB): [ka] The compound described in item 79 above, which is a compound of the above. (Section 84) The compound of formula (I) is of formula (IC): [ka] The compound described in item 79 above, which is a compound of the above. (Section 85) The compound of formula (I) is of formula (IE), (IF), or (IG): [ka] [ka] [In the formula, R 2C is hydrogen or alkyl, and R 3 is alkyl, alkenyl, alkynyl or -OR A And here, R A The compound described in item 79 above, which is an alkyl compound. (Section 86) The compound of formula (I) is formula (IH), (II), or (IJ): [ka] [In the formula, R 3 is alkyl, alkenyl, alkynyl or -OR A And here, R A The compound described in item 79 above, which is an alkyl compound. (Section 87) The compound of formula (I) is of formula (IK): [ka] [In the formula, R 3 is alkyl, alkenyl, alkynyl or -OR A And here, R A The compound described in item 79 above, which is an alkyl compound. (Section 88) The compound of formula (I) is of formula (IM) [ka] [In the formula, R' is alkyl or -OR A And here, R AThe compound described in item 79 above, which is a compound of [where is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, or 3]. (Section 89) R 1A and R 1B Each of the compounds is independently an unsubstituted or substituted alkyl group, as described in any one of items 79 to 87 above. (Section 90) R 1A and R 1B Each of these is a compound according to any one of the above items 79 to 87, independently selected from the group consisting of haloalkyl, alkoxyalkyl, -CH3, -CH2CH3, -CH(CH3)2, -CF3, and -CH2OCH3. (Section 91) R 1A and R 1B Each of the compounds is independently a substituted alkyl group, as described in any one of items 79 to 87 above. (Section 92) R 1A and R 1B Each of the compounds is independently a haloalkyl, as described in any one of items 79 to 87 above. (Section 93) R 1A The compound is one of the compounds described in any one of items 79 to 87 above, wherein the compound is -CF3 or -CH2OCH3. (Section 94) R 1A and R 1B The compound described in any one of items 79 to 87 above, wherein is an unsubstituted or substituted alkyl group. (Section 95) R 1A and R 1B A compound described in any one of items 79 to 87 above, wherein is -CH3. (Section 96) R 1A and R 1B The compound described in any one of items 79 to 87 above, wherein they form a 3- to 8-membered ring together with the carbon atoms to which they are bonded. (Section 97) R 1Ais hydrogen, and R 1B The compound is an alkyl, carbocyryl, heterocyclyl, aryl, or heteroaryl compound as described in any one of items 79 to 87 above. (Section 98) R 1A is a substituted alkyl or unsubstituted C2-C6 alkyl, and R 1B The compound is a substituted or unsubstituted C1-C6 alkyl group, as described in any one of items 79 to 87 above. (Section 99) R 2A and R 2B Each of them independently is a substituted or unsubstituted alkyl, as described in section 79 above. A compound listed in any one of item 88. (Section 100) R 2A and R 2B Each of them is independently -F, the compound described in any one of items 79 to 88 above. (Section 101) R 2A and R 2B is -CH3, and R 3 is alkyl, alkenyl, alkynyl or -OR A And here, R A A compound described in any one of items 79 to 88 above, wherein is alkyl. (Section 102) R 2A and R 2B A compound described in any one of items 79 to 88 above, wherein is -F. (Section 103) R 3 This includes substituted or unsubstituted alkyl, alkenyl, alkynyl, or -OR A And here, R A A compound described in any one of items 79 to 88 above, wherein is alkyl. (Section 104) R 3 The compound according to any one of items 79 to 88 above, wherein is a substituted alkyl or an unsubstituted alkyl. (Section 105) R2A and R 2B Each of them is independently hydrogen, and R 3 The compound according to any one of items 79 to 88 above, wherein is a substituted or unsubstituted alkyl group. (Section 106) A pharmaceutical composition comprising the compound described in item 79 above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. (Section 107) A method for inducing sedation or anesthesia, comprising the step of administering to a subject an effective amount of the compound described in item 79 above or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition thereof. (Section 108) A method for treating or preventing any of the disorders described herein, comprising the step of administering an effective amount of the compound described in item 79 above or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition thereof to a subject in need of such treatment or prevention. (Section 109) The method according to item 108, wherein the disorder is a gastrointestinal (GI) disorder, constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, structural disorders affecting the GI, anal disorders, hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas, colon polyps, cancer, or colitis. (Section 110) The method described in item 108 above, wherein the disorder is inflammatory bowel disease. (Section 111) The method according to item 108, wherein the disorder is cancer, diabetes, or sterol synthesis disorder. (Section 112) The method described in item 108 above, wherein the disorder is a metabolic disorder. (Section 113) The method described in item 108 above, wherein the disorder is an autoimmune disorder. (Section 114) The method according to item 108, wherein the aforementioned disorders are rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and psoriasis vulgaris. (Section 115) A method for treating or preventing a CNS-related condition, comprising, to a subject in need of such treatment or prevention, an effective amount of the compound described in item 79 above or a pharmaceutically acceptable A method comprising the step of administering a salt or a pharmaceutical composition thereof. (Section 116) The aforementioned CNS-related conditions include adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, and social phobia), cognitive impairments (including Alzheimer's disease and other forms of dementia), dissociative disorders, eating disorders, mood disorders (including depression or postpartum depression, bipolar disorder, dysthymic disorder, and suicidal tendencies), schizophrenia or other psychotic disorders (including schizoaffective psychosis), sleep disorders (including insomnia), substance-related disorders, personality disorders (including obsessive-compulsive personality disorder), and autism spectrum disorders (mutations in the Shank group protein (Shank3)). The method according to item 115 above, which includes, for example, neurodevelopmental disorders (such as Rett syndrome and tuberous sclerosis complex), multiple sclerosis, sterol synthesis disorders, pain (such as acute and chronic pain), secondary brain damage to a certain medical condition (such as hepatic encephalopathy and anti-NMDA receptor encephalitis), paroxysmal disorders (such as status epilepticus and monogenic epilepsy, e.g., Dravet disease), stroke, traumatic brain injury, motor impairment (such as Huntington's disease and Parkinson's disease), visual impairment, hearing impairment, or tinnitus. (Section 117) The method according to item 108, wherein the impairment is a sterol synthesis disorder. (Section 118) Formula (II): [ka] [In the formula, R 1A and R 1B Each of them independently is hydrogen, a substituted or unsubstituted alkyl, a carbocyacrylic, a heterocycline, an aryl or heteroaryl, or R 1A and R 1BThey form a 3- to 8-membered ring together with the carbon atoms to which they are bonded; R 2A and R 2B Each of these is independently hydrogen, halo, -OR C , alkyl, alkenyl, alkynyl, aryl or heteroaryl, where R C is either hydrogen or alkyl, or R 2A and R 2B They form an oxo group together with the carbon atoms to which they are bonded, and here, R 2A and R 2B Both are not hydrogen at the same time; R 3 This includes hydrogen, alkyl, alkenyl, alkynyl or -OR A And here, R A It is alkyl; R 4 It does not exist, or it is hydrogen; and [ka] represents a single bond or a double bond, where, [ka] If one of them is a double bond, the other [ka] It is a single bond; [ka] If both are single bonds, R 4 is hydrogen; and [ka] If one of them is a double bond, R 4 It does not exist; However, R 4 R does not exist, 2A is -OH, and R 2B is hydrogen or -CF3, and R1A and R 1B If R is -CH3, 3 It is not hydrogen; and R 1A and R 1B is -CH3, and R 3 If R is hydrogen, 2A and R 2B Compounds of which do not form an oxo group with the carbon atoms to which they are bonded, or pharmaceutically acceptable salts thereof. (Section 119) R 4 It does not exist, R 2A and R 2B One of them is -OH, and R 3 The compound described in item 118 above is not hydrogen. (Section 120) The compound of formula (II) is formula (II-A): [ka] The compound described in item 118 above, which is a compound of the above. (Section 121) The compound of formula (II) is formula (II-B): [ka] The compound described in item 118 above, which is a compound of the above. (Section 122) The compound of formula (II) is formula (II-C): [ka] The compound described in item 118 above, which is a compound of the above. (Section 123) The compound of formula (II) is formula (II-D): [ka] The compound described in item 118 above, which is a compound of the above. (Section 124) The compounds of formula (II) are formulas (II-E), (II-F), or (II-G): [ka] [In the formula, R 2C is hydrogen or a substituted or unsubstituted alkyl, and R 3 The compound described in item 118 above, which is a compound of [a substituted alkyl or an unsubstituted alkyl]. (Section 125) The compound of formula (II) is (II-H), (II-I), or (II-J): [ka] [In the formula, R 3 is alkyl, alkenyl, alkynyl or -OR A And here, R A The compound described in item 118 above, which is an alkyl compound. (Section 126) The compound of formula (II) is of formula (II-K) [ka] [In the formula, R' is alkyl or -OR A And here, R A The compound described in item 118 above, which is a compound of [where is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, or 3]. (Section 127) R 1A and R 1B Each of the compounds is independently an unsubstituted or substituted alkyl group, as described in any one of items 118 to 125 above. (Section 128) R 1A and R 1B This is a compound independently selected from the group consisting of haloalkyl, alkoxyalkyl, -CH3, -CH2CH3, -CH(CH3)2, -CF3, and -CH2OCH3, as described in any one of items 118 to 125 above. (Section 129) R 1A and R1B Each of the compounds is independently a substituted alkyl group, as described in any one of items 118 to 125 above. (Section 130) R 1A and R 1B Each of the compounds is a haloalkyl, as described in item 129 above. (Section 131) R 1A The compound is one of the compounds described in any one of sections 118 to 125 above, wherein the compound is -CF3 or -CH2OCH3. (Section 132) R 1A and R 1B The compound described in any one of items 118 to 125 above, wherein is an unsubstituted or substituted alkyl group. (Section 133) R 1A and R 1B A compound described in any one of items 118 to 125 above, wherein is -CH3. (Section 134) R 1A and R 1B The compounds described in any one of items 118 to 125 above, wherein they form a ring together with the carbon atoms to which they are bonded. (Section 135) R 1A is hydrogen, and R 1B The compound is an alkyl, carbocyryl, heterocyclyl, aryl, or heteroaryl compound as described in any one of items 118 to 125 above. (Section 136) R 2A and R 2B Each of the compounds is independently a substituted or unsubstituted alkyl group, as described in any one of items 118 to 126 above. (Section 137) R 3 The compound is one of the compounds described in any one of items 118 to 126 above, wherein the compound is a substituted alkyl or an unsubstituted alkyl. (Section 138) R 2A and R 2B Each of them is independently hydrogen, and R 3The compound according to any one of items 118 to 126 above, wherein is a substituted or unsubstituted alkyl group. (Section 139) R 2A and R 2B Each of the compounds is independently -F, as described in any one of items 118 to 126 above. (Section 140) R 2A and R 2B is -CH3, and R 3 is alkyl, alkenyl, alkynyl or -OR A And here, R A A compound described in any one of items 118 to 126 above, wherein is alkyl. (Section 141) R 2A and R 2B A compound described in any one of items 118 to 126 above, wherein is -F. (Section 142) R 1A is a substituted alkyl or unsubstituted C2-C6 alkyl, and R 1B The compound is a substituted or unsubstituted C1-C6 alkyl group, as described in any one of items 118 to 125 above. (Section 143) A pharmaceutical composition comprising the compound described in item 118 above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. (Section 144) A method for inducing sedation or anesthesia, comprising the step of administering to a subject an effective amount of the compound described in item 118 above or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition thereof. (Section 145) A method for treating or preventing any of the disorders described herein, comprising the step of administering an effective amount of the compound described in item 118 or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition thereof to a subject in need of such treatment or prevention. (Section 146) The method according to item 145, wherein the disorder is a gastrointestinal (GI) disorder, constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, structural disorders affecting the GI, anal disorders, hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas, colon polyps, cancer, or colitis. (Section 147) The method described in item 145 above, wherein the disorder is inflammatory bowel disease. (Section 148) The method according to item 145, wherein the disorder is cancer, diabetes, or sterol synthesis disorder. (Section 149) The method described in paragraph 145 above, wherein the disorder is a metabolic disorder. (Section 150) The method described in paragraph 145 above, wherein the disorder is an autoimmune disorder. (Section 151) The method according to item 145, wherein the aforementioned disorders are rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and psoriasis vulgaris. (Section 152) A method for treating or preventing a CNS-related condition, comprising the step of administering an effective amount of the compound described in item 118 above or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition thereof to a subject in need of such treatment or prevention. (Section 153) The aforementioned CNS-related conditions include adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, and social phobia), cognitive impairments (including Alzheimer's disease and other forms of dementia), dissociative disorders, eating disorders, mood disorders (including depression and postpartum depression), bipolar disorder, dysthymic disorder, suicidal tendencies, schizophrenia, or other psychotic disorders (schizophrenia). The method described in paragraph 152 above, which includes mental illness, sleep disorders (such as insomnia), substance-related disorders, personality disorders (such as obsessive-compulsive personality disorder), autism spectrum disorders (such as those involving mutations in the Shank group proteins (Shank3)), neurodevelopmental disorders (such as Rett syndrome and tuberous sclerosis complex), multiple sclerosis, sterol synthesis disorders, pain (such as acute and chronic pain), secondary brain damage to a certain medical condition (such as hepatic encephalopathy and anti-NMDA receptor encephalitis), paroxysmal disorders (such as status epilepticus and monogenic epilepsy, e.g., Dravet disease), stroke, traumatic brain injury, motor disorders (such as Huntington's disease and Parkinson's disease), visual impairment, hearing impairment, or tinnitus. (Section 154) The method according to item 145, wherein the impairment is a sterol synthesis disorder. (Section 155) Formula (III): [ka] [In the formula, R 1A and R 1B Each of them is a substituted or unsubstituted alkyl group; R 2A and R 2B Each of them independently contains hydrogen, -OR C or alkyl, where R C is either hydrogen or alkyl, or R 2A and R 2B They form an oxo group together with the carbon atoms to which they are bonded, and here, R 2A and R 2B Both are not hydrogen at the same time; R 3 It is alkyl; R 4 It does not exist, or it is hydrogen; and [ka] represents a single bond or a double bond, where, [ka] If one of them is a double bond, the other [ka] It is a single bond; [ka] If both are single bonds, R 4 is hydrogen; and [ka] If one of them is a double bond, R 4 [The compound or a pharmaceutically acceptable salt of the compound does not exist.] (Section 156) R 1A and R 1B Each of the compounds is -CH3, as described in item 155 above. (Section 157) R 2A and R 2B The compound described in item 155 above, wherein they form an oxo group together with the carbon atoms to which they are bonded. (Section 158) R 3 The compound described in item 155 above, wherein is -CH2CH3. (Section 159) R 2A is -OH, and R 2B The compound described in item 155 above, wherein is H. (Section 160) R 2A is -CH3, and R 2B The compound described in item 155 above, wherein is H. (Section 161) R 2A is -OH, and R 2B The compound described in item 155 above, wherein is -CH3. (Item 162) R 1A The compound described in item 155 above, wherein is -CF3. (Section 163) A pharmaceutical composition comprising the compound described in item 155 above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. (Section 164) A method for inducing sedation or anesthesia, comprising the step of administering to a subject an effective amount of the compound described in item 155 above or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition thereof. (Section 165) A method for treating or preventing any of the disorders described herein, comprising the step of administering an effective amount of the compound described in item 155 above or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition thereof to a subject in need of such treatment or prevention. (Section 166) The method according to item 165, wherein the disorder is a gastrointestinal (GI) disorder, constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, structural disorders affecting the GI, anal disorders, hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas, colon polyps, cancer, or colitis. (Section 167) The method according to item 165 above, wherein the disorder is inflammatory bowel disease. (Section 168) The method according to item 165, wherein the disorder is cancer, diabetes, or sterol synthesis disorder. (Section 169) The method described in paragraph 165 above, wherein the disorder is a metabolic disorder. (Section 170) The method described in paragraph 165 above, wherein the disorder is an autoimmune disorder. (Section 171) The method according to item 165, wherein the aforementioned disorders are rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and psoriasis vulgaris. (Section 172) A method for treating or preventing a CNS-related condition, comprising the step of administering an effective amount of the compound described in item 155 above or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable composition thereof to a subject in need of such treatment or prevention. (Section 173) The aforementioned CNS-related conditions include adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, and social phobia), cognitive impairments (including Alzheimer's disease and other forms of dementia), dissociative disorders, eating disorders, mood disorders (including depression and postpartum depression), bipolar disorder, dysthymic disorder, and suicidal tendencies), schizophrenia or other psychotic disorders (including schizoaffective psychosis), sleep disorders (including insomnia), substance-related disorders, personality disorders (including obsessive-compulsive personality disorder), and autism spectrum disorders (including mutations in Shank group proteins (Shank3)). The method described in paragraph 172 above, which includes, among others, neurodevelopmental disorders (including Rett syndrome and tuberous sclerosis complex), multiple sclerosis, sterol synthesis disorders, pain (including acute and chronic pain), secondary brain damage to a certain medical condition (including hepatic encephalopathy and anti-NMDA receptor encephalitis), paroxysmal disorders (including status epilepticus and monogenic epilepsy, e.g., Dravet disease), stroke, traumatic brain injury, motor disorders (including Huntington's disease and Parkinson's disease), visual impairment, hearing impairment, or tinnitus. (Section 174) The method according to item 165, wherein the impairment is a sterol synthesis disorder.

Claims

[Claim 1] A state relating to the expression and function of NMDA.

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