C7-substituted oxysterols and methods of use as nmda modulators

Abstract

The present application relates to C7 substituted oxysterols and methods of use thereof as NMDA modulators. Specifically, provided herein are compounds of Formula (A) and pharmaceutically acceptable salts thereof and pharmaceutical compositions thereof; wherein R 1A , R 1B , n, R 2A , R 2B , R 3 , and R 4 are as defined herein. The compounds of the present application are contemplated for use in the prevention and treatment of various disorders.

Description

[0001] This application is a divisional application of Chinese invention patent application (application date: September 30, 2017; application number: 201780072617.6 (international application number: PCT / US2017 / 054657); invention title: C7 substituted oxosterols and methods thereof as NMDA modifiers).

[0002] Related applications

[0003] 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 September 30, 2016, each of which is incorporated herein by reference. Background Technology

[0004] NMDA receptors are heteropolymeric complexes composed of NR1, NR2, and / or NR3 subunits, and possess different recognition sites for exogenous and endogenous ligands. These recognition sites include binding sites for glycine and glutamate agonists and modulators. NMDA receptors are expressed in peripheral tissues and the CNS, where they are involved in excitatory synaptic transmission. Activation of these receptors contributes to synaptic plasticity in some cases and excitatory toxicity in others. These receptors are ligand-gated ion channels that allow Ca2+ ionization upon binding to glutamate and glycine. 2+ Glutamate transmission is fundamental to excitatory neurotransmission and normal CNS function. Positive modulators can be used as therapeutic agents with potential clinical applications, as cognitive enhancers, and for the treatment of mental disorders with reduced or deficient glutamatergic transmission (see, for example, Horak et al., J. of Neuroscience, 2004, 24(46), 10318-10325). Conversely, negative modulators can be used as therapeutic agents with potential clinical applications for the treatment of mental disorders in which glutamatergic transmission is pathologically increased (e.g., for the treatment of resistant depression).

[0005] Oxisterols are cholesterol analogs and regulators of NMDA receptor function. Novel oxosterol-mediated NMDA receptor modulations are needed for the prevention and treatment of conditions associated with NMDA expression and function. The compounds, compositions, and methods described herein are for this purpose. Summary of the Invention

[0006] This document provides substituted oxosterols that can be used to prevent and / or treat a variety of diseases, including but not limited to NMDA-mediated diseases. Pharmaceutical compositions comprising the compounds of this invention are also provided, as well as their uses and treatment methods.

[0007] In one respect, this paper provides compounds of formula (A):

[0008]

[0009] Or its pharmaceutically acceptable salt, wherein:

[0010] R 1A and R 1B Each of the following is independently hydrogen, substituted or unsubstituted alkyl, carbocyclic, heterocyclic, aryl or heteroaryl, or R. 1A and R 1B Together with the carbon atoms they are attached to, they form 3-8 membered rings;

[0011] n is 1 or 2;

[0012] R 2A and R 2B Each independently represents hydrogen, halogen, –OR C alkyl, alkenyl, alkynyl, aryl or heteroaryl, wherein R C It is hydrogen or alkyl or R 2A and R 2B Together with the carbon atoms they are attached to, they form oxo groups, where R 2A and R 2B They are not both hydrogen;

[0013] R 3 It can be hydrogen, alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group;

[0014] R 4 It is either non-existent or is hydrogen; and

[0015] Represents a single bond or a double bond, where when one When it is a double bond, then the other one... For a single bond; when two When all bonds are single bonds, then R 4 For hydrogen; and when one When it is a double bond, R 4 It does not exist.

[0016] In some implementations, n is 1. In other implementations, n is 2.

[0017] In some implementations, when R 1A R 3 and R 4 It is hydrogen and R 1B When it is an unsubstituted isopropyl group, then R 2A and R 2B They do not form oxo groups together with the carbon atoms they are attached to; and when R 4 It does not exist, R 3 For hydrogen and R 1A and R 1BWhen it is –CH3, then R 2A Not for –CH3 and R 2B Not –OH. In other implementations, n is 1.

[0018] In some implementations, when R 4 It does not exist, R 2A For –OH, R 2B For hydrogen or –CF3 and R 1A and R 1B When it is –CH3, then R 3 Not hydrogen; and when R 1A and R 1B For –CH3 and R 3 When it is hydrogen, then R 2A and R 2B They do not form oxo groups together with the carbon atoms they are attached to. In other embodiments, n is 2.

[0019] In some embodiments, the compound of formula (A) is a compound of formula (AI):

[0020]

[0021] In some embodiments, compound (A) is compound (A-II):

[0022]

[0023] In some embodiments, compound (A) is a compound of formula (A-III):

[0024]

[0025] In some embodiments, the compound of formula (A) is a compound of formula (A-IV), (AV), or (A-VI):

[0026]

[0027] Where R 2C Hydrogen or alkyl and R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group.

[0028] In some embodiments, the compound of formula (A) is a compound of formula (A-VII), (A-VIII), or (A-IX):

[0029]

[0030] Where R 3 It is alkyl, alkenyl, ynyl or –ORA , where R A It is an alkyl group.

[0031] In some embodiments, the compound of formula (A) is a compound of formula (AX):

[0032]

[0033] Where R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group.

[0034] In some embodiments, the compound of formula (A) is a compound of formula (A-XII).

[0035]

[0036] Where R' is an alkyl group or –OR A , where R A It is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5 or 6; and m is 0, 1, 2 or 3.

[0037] In some implementation schemes, R 4 It does not exist, R 2A and R 2B One of them is –OH and R 3 It is not hydrogen.

[0038] In some implementation schemes, R 1A and R 1B Each is independently an unsubstituted or substituted alkyl group (e.g., haloalkyl, alkoxyalkyl, –CH3, –CH2CH3, –CH(CH3)2, –CF3 or –CH2OCH3).

[0039] In other implementations, R 1A and R 1B Each is independently a substituted alkyl group (e.g., a haloalkyl group). In some embodiments, R 1A and R 1B It is an alkyl group (e.g., unsubstituted or substituted alkyl groups (e.g., –CH3)). In some embodiments, R 1A and R 1B It is –CH3.

[0040] In some respects, R 1A It can be –CF3 or –CH2OCH3.

[0041] In other respects, R 1A For hydrogen and R 1B It can be alkyl, carbocyclic, heterocyclic, aryl, or heteroaryl.

[0042] In some implementation schemes, R 1A and R 1B Together with the carbon atoms they are attached to, they form 3-8 membered rings.

[0043] In some respects, R 1A For substituted alkyl or unsubstituted C2-C6 alkyl and R 1B It is a substituted or unsubstituted C1-C6 alkyl group.

[0044] In some implementation schemes, R 2A and R 2B Each is independently an alkyl group (e.g., substituted or unsubstituted alkyl). In some respects, R 2A and R 2B Each is independently represented by –F.

[0045] In other implementations, R 2A and R 2B For –CH3 and R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group. In some other embodiments, R 2A and R 2B Each independently consists of hydrogen and R 3 It is an alkyl group (e.g., substituted or unsubstituted alkyl).

[0046] In some implementations, R 3 It is an alkyl (e.g., substituted or unsubstituted alkyl), alkenyl, ynyl, or –OR A , where R A It is an alkyl group. In other embodiments, R 3 It is an alkyl group (e.g., substituted or unsubstituted alkyl).

[0047] In one respect, this paper provides compounds of formula (B):

[0048]

[0049] Or its pharmaceutically acceptable salt, wherein:

[0050] R 1A and R 1B Each of the following is independently hydrogen, substituted or unsubstituted alkyl, carbocyclic, heterocyclic, aryl or heteroaryl, or R. 1A and R 1B Together with the carbon atoms they are attached to, they form 3-8 membered rings;

[0051] n is 1 or 2;

[0052] R 2A and R2B Each independently represents hydrogen, halogen, –OR C alkyl, alkenyl, alkynyl, aryl or heteroaryl, wherein R C It is hydrogen or alkyl or R 2A and R 2B Together with the carbon atoms they are attached to, they form oxo groups, where R 2A and R 2B They are not both hydrogen;

[0053] R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group;

[0054] R 4 It is either non-existent or is hydrogen; and

[0055] Represents a single bond or a double bond, where when one When it is a double bond, then the other one... For a single bond; when two When all bonds are single bonds, then R 4 For hydrogen; and when one When it is a double bond, R 4 It does not exist.

[0056] In some implementations, n is 1. In other implementations, n is 2.

[0057] In some embodiments, the compound of formula (B) is a compound of formula (BI):

[0058]

[0059] In some embodiments, the compound of formula (B) is a compound of formula (B-II):

[0060]

[0061] In some embodiments, the compound of formula (B) is a compound of formula (B-III):

[0062]

[0063] In some embodiments, the compound of formula (B) is a compound of formula (B-IV), (BV), or (B-VI):

[0064]

[0065] Where R 2C Hydrogen or alkyl and R 3 It is alkyl, alkenyl, ynyl or –OR A, where R A It is an alkyl group.

[0066] In some embodiments, the compound of formula (B) is a compound of formula (B-VII), (B-VIII), or (B-IX):

[0067]

[0068] Where R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group.

[0069] In some embodiments, the compound of formula (B) is a compound of formula (BX):

[0070]

[0071] Where R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group.

[0072] In some embodiments, the compound of formula (B) is a compound of formula (B-XII).

[0073]

[0074] Where R' is an alkyl group or –OR A , where R A It is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5 or 6; and m is 0, 1, 2 or 3.

[0075] In some implementation schemes, R 1A and R 1B Each is independently an unsubstituted or substituted alkyl group (e.g., haloalkyl, alkoxyalkyl, –CH3, –CH2CH3, –CH(CH3)2, –CF3 or –CH2OCH3).

[0076] In other implementations, R 1A and R 1B Each is independently a substituted alkyl group (e.g., a haloalkyl group). In some embodiments, R 1A and R 1B It is an alkyl group (e.g., unsubstituted or substituted alkyl groups (e.g., –CH3)). In some embodiments, R 1A and R 1B It is –CH3.

[0077] In some respects, R 1A It can be –CF3 or –CH2OCH3.

[0078] In other respects, R 1A For hydrogen and R 1B It can be alkyl, carbocyclic, heterocyclic, aryl, or heteroaryl.

[0079] In some implementation schemes, R 1A and R 1B Together with the carbon atoms they are attached to, they form 3-8 membered rings.

[0080] In some respects, R 1A For substituted alkyl or unsubstituted C2-C6 alkyl and R 1B It is a substituted or unsubstituted C1-C6 alkyl group.

[0081] In some implementation schemes, R 2A and R 2B Each is independently an alkyl group (e.g., substituted or unsubstituted alkyl). In some respects, R 2A and R 2B Each is independently represented by –F.

[0082] In other implementations, R 2A and R 2B For –CH3 and R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group. In some other embodiments, R 2A and R 2B Each independently consists of hydrogen and R 3 It is an alkyl group (e.g., substituted or unsubstituted alkyl).

[0083] In some implementations, R 3 It is an alkyl (e.g., substituted or unsubstituted alkyl), alkenyl, ynyl, or –OR A , where R A It is an alkyl group. In other embodiments, R 3 It is an alkyl group (e.g., substituted or unsubstituted alkyl).

[0084] In one respect, this paper provides compounds of formula (I):

[0085]

[0086] Or its pharmaceutically acceptable salt, wherein:

[0087] R 1A and R 1B Each of the following is independently hydrogen, substituted or unsubstituted alkyl, carbocyclic, heterocyclic, aryl or heteroaryl, or R. 1A and R 1B Together with the carbon atoms they are attached to, they form 3-8 membered rings;

[0088] R 2A and R 2B Each independently represents hydrogen, halogen, –OR C alkyl, alkenyl, alkynyl, aryl or heteroaryl, wherein R C It is hydrogen or alkyl or R 2A and R 2B Together with the carbon atoms they are attached to, they form oxo groups, where R 2A and R 2B They are not both hydrogen;

[0089] R 3 It can be hydrogen, alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group;

[0090] R 4 It is either non-existent or is hydrogen; and

[0091] Represents a single bond or a double bond, where when one When it is a double bond, then the other one... For a single bond; when two When all bonds are single bonds, then R 4 For hydrogen; and when one When it is a double bond, R 4 It does not exist;

[0092] Where R 1A R 3 and R 4 For hydrogen and R 1B If it is an unsubstituted isopropyl group, then R 2A and R 2B They do not form oxo groups together with the carbon atoms they are attached to; and

[0093] When R 4 It does not exist, R 3 For hydrogen and R 1A and R 1B If it is –CH3, then R 2A Not for –CH3 and R 2B Not –OH.

[0094] In some implementation schemes, R 1A R 3 and R 4 For hydrogen, R 1B For unsubstituted isopropyl and R 2A and R 2B They do not form oxo groups together with the carbon atoms they are attached to.

[0095] In some implementation schemes, R4 It does not exist, R 3 For hydrogen, R 1A and R 1B For –CH3, R 2A Not for –CH3 and R 2B Not –OH.

[0096] In some embodiments, the compound of formula (I) is a compound of formula (IA):

[0097]

[0098] In some embodiments, the compound of formula (I) is a compound of formula (IB):

[0099]

[0100] In some embodiments, the compound of formula (I) is a compound of formula (IC):

[0101]

[0102] In some embodiments, the compound of formula (I) is a compound of formula (IE), (IF), or (IG):

[0103]

[0104] Where R 2C Hydrogen or alkyl and R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group.

[0105] In some embodiments, the compound of formula (I) is a compound of formula (IH), (II), or (IJ):

[0106]

[0107] Where R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group.

[0108] In some embodiments, the compound of formula (I) is a compound of formula (IK):

[0109]

[0110] Where R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group.

[0111] In some embodiments, the compound of formula (I) is a compound of formula (IM):

[0112]

[0113] Where R' is an alkyl group or –OR A , where R A It is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5 or 6; and m is 0, 1, 2 or 3.

[0114] In some implementation schemes, R 1A and R 1B Each is independently an unsubstituted or substituted alkyl group (e.g., haloalkyl, alkoxyalkyl, –CH3, –CH2CH3, –CH(CH3)2, –CF3 or –CH2OCH3).

[0115] In some implementation schemes, R 1A and R 1B Each is independently a substituted alkyl group (e.g., a haloalkyl group).

[0116] In some implementation schemes, R 1A It can be –CF3 or –CH2OCH3.

[0117] In some implementation schemes, R 1A and R 1B It is an alkyl group (e.g., unsubstituted or substituted alkyl groups (e.g., –CH3)).

[0118] In some implementation schemes, R 1A and R 1B It is –CH3.

[0119] In some implementation schemes, R 1A and R 1B Together with the carbon atoms they are attached to, they form 3-8 membered rings.

[0120] In some implementation schemes, R 1A For hydrogen and R 1B It can be alkyl, carbocyclic, heterocyclic, aryl, or heteroaryl.

[0121] In some implementation schemes, R 1A For substituted alkyl or unsubstituted C2-C6 alkyl and R 1B It is a substituted or unsubstituted C1-C6 alkyl group.

[0122] In some implementation schemes, R 2A and R 2B Each is an alkyl group (e.g., substituted or unsubstituted alkyl groups).

[0123] In some implementation schemes, R 2A and R 2B Each is independently represented by –F.

[0124] In some implementation schemes, R 2A and R 2B For –CH3 and R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group.

[0125] In some implementation schemes, R 2A and R 2B For –F.

[0126] In some implementation schemes, R 3 It is an alkyl (e.g., substituted or unsubstituted alkyl), alkenyl, ynyl, or –OR A , where R A It is an alkyl group.

[0127] In some implementation schemes, R 3 It is an alkyl group (e.g., substituted or unsubstituted alkyl).

[0128] In some implementation schemes, R 2A and R 2B Each independently consists of hydrogen and R 3 It is an alkyl group (e.g., substituted or unsubstituted alkyl).

[0129] In one respect, this paper provides compounds of formula (II):

[0130]

[0131] Or its pharmaceutically acceptable salt, wherein:

[0132] R 1A and R 1B Each of the following is independently hydrogen, substituted or unsubstituted alkyl, carbocyclic, heterocyclic, aryl or heteroaryl, or R. 1A and R 1B Together with the carbon atoms they are attached to, they form 3-8 membered rings;

[0133] R 2A and R 2B Each independently represents hydrogen, halogen, –OR C alkyl, alkenyl, alkynyl, aryl or heteroaryl, wherein R C It is hydrogen or alkyl or R 2A and R 2B Together with the carbon atoms they are attached to, they form oxo groups, where R 2A and R 2B They are not both hydrogen;

[0134] R 3 It can be hydrogen, alkyl, alkenyl, ynyl or –OR A ,in

[0135] R A It is an alkyl group;

[0136] R 4 It is either non-existent or is hydrogen; and

[0137] Represents a single bond or a double bond, where when one When it is a double bond, then the other one... For a single bond; when two When all bonds are single bonds, then R 4 For hydrogen; and when one When it is a double bond, R 4 It does not exist;

[0138] The premise is that when R 4 It does not exist, R 2A For –OH, R 2B For hydrogen or –CF3 and R 1A and R 1B When it is –CH3, then R 3 Not hydrogen; and

[0139] When R 1A and R 1B For –CH3 and R 3 When it is hydrogen, then R 2A and R 2B They do not form oxo groups together with the carbon atoms they are attached to.

[0140] In some implementation schemes, R 4 It does not exist, R 2A and R 2B One of them is –OH and R 3 It is not hydrogen.

[0141] In some embodiments, the compound of formula (II) is a compound of formula (II-A):

[0142]

[0143] In some embodiments, the compound of formula (II) is a compound of formula (II-B):

[0144]

[0145] In some embodiments, the compound of formula (II) is a compound of formula (II-C):

[0146]

[0147] In some embodiments, the compound of formula (II) is a compound of formula (II-D):

[0148]

[0149] In some embodiments, the compound of formula (II) is a compound of formula (II-E), (II-F), or (II-G):

[0150]

[0151] Where R 2C It is hydrogen or alkyl (e.g., substituted or unsubstituted alkyl) and R 3 It is an alkyl group (e.g., substituted or unsubstituted alkyl).

[0152] In some embodiments, the compound of formula (II) is a compound of formula (II-H), (II-I), or (II-J):

[0153]

[0154] Where R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group.

[0155] In some embodiments, the compound of formula (II) is a compound of formula (II-K):

[0156]

[0157] Where R' is an alkyl group or –OR A , where R A It is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5 or 6; and m is 0, 1, 2 or 3.

[0158] In some implementation schemes, R 1A and R 1B Each is independently an unsubstituted or substituted alkyl group (e.g., haloalkyl, alkoxyalkyl, –CH3, –CH2CH3, –CH(CH3)2, –CF3 or –CH2OCH3).

[0159] In some implementation schemes, R 1A and R 1B Each is independently a substituted alkyl group (e.g., a haloalkyl group).

[0160] In some implementation schemes, R 1A It can be –CF3 or –CH2OCH3.

[0161] In some implementation schemes, R 1A and R 1B It is an alkyl group (e.g., unsubstituted or substituted alkyl groups (e.g., –CH3)).

[0162] In some implementation schemes, R 1A and R 1B It is –CH3.

[0163] In some implementation schemes, R 1A and R 1B They form rings together with the carbon atoms they are attached to.

[0164] In some implementation schemes, R 1A For hydrogen and R 1B It can be alkyl, carbocyclic, heterocyclic, aryl, or heteroaryl.

[0165] In some implementation schemes, R 2A and R 2B Each is an alkyl group (e.g., substituted or unsubstituted alkyl groups).

[0166] In some implementation schemes, R 3 It is an alkyl group (e.g., substituted or unsubstituted alkyl).

[0167] In some implementation schemes, R 2A and R 2B Each independently consists of hydrogen and R 3 It is an alkyl group (e.g., substituted or unsubstituted alkyl).

[0168] In some implementation schemes, R 2A and R 2B Each is independently represented by –F.

[0169] In some implementation schemes, R 2A and R 2B For –CH3 and R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group.

[0170] In some implementation schemes, R 2A and R 2B For –F.

[0171] In some implementation schemes, R 1A For substituted alkyl or unsubstituted C2-C6 alkyl and R 1B It is a substituted or unsubstituted C1-C6 alkyl group.

[0172] In some respects, the compound is a compound of formula (III):

[0173]

[0174] Or its pharmaceutically acceptable salt, wherein:

[0175] R 1A and R 1B Each is a substituted or unsubstituted alkyl group;

[0176] R 2A and R 2B Each independently is hydrogen, –OR C or alkyl, wherein R C It is hydrogen or alkyl, or

[0177] R 2A and R 2B Together with the carbon atoms they are attached to, they form oxo groups, where R 2A and R 2B They are not both hydrogen;

[0178] R 3 It is an alkyl group;

[0179] R 4 It is either non-existent or is hydrogen; and

[0180] Represents a single bond or a double bond, where when one When it is a double bond, then the other one... For a single bond; when two When all bonds are single bonds, then R 4 For hydrogen; and when one When it is a double bond, R 4 It does not exist.

[0181] In some implementation schemes, R 1A and R 1B Each is –CH3.

[0182] In some implementation schemes, R 2A and R 2B Together with the carbon atoms they are attached to, they form oxo groups.

[0183] In some implementation schemes, R 3 It is –CH2CH3.

[0184] In some implementation schemes, R 2A For –OH and R 2B For H.

[0185] In some implementation schemes, R 2A For –CH3 and R 2B For H.

[0186] In some implementation schemes, R 2A For –OH and R 2B It is –CH3.

[0187] In some implementation schemes, R 1A For –CF3.

[0188] In one aspect, this document provides pharmaceutical compositions comprising the compounds described herein or pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers.

[0189] In one aspect, this article provides methods for inducing sedation or anesthesia, which include administering to a subject an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0190] In one aspect, this article provides methods for treating or preventing the conditions described herein, including administering to a subject in need an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0191] In some implementations, the condition is an autoimmune disease.

[0192] In some implementations, the condition is rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and plaque psoriasis.

[0193] In some implementations, the condition is a metabolic disorder.

[0194] In some implementations, the condition is a gastrointestinal (GI) condition such as constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) (e.g., ulcerative colitis, Crohn's disease), a structural condition affecting the gastrointestinal tract, anal conditions (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas), colonic polyps, cancer, or colitis.

[0195] In some implementations, the condition is inflammatory bowel disease.

[0196] In some implementations, the condition is cancer, diabetes, or a sterol synthesis disorder.

[0197] In one aspect, this document provides methods for treating or preventing CNS-related disorders, comprising administering to a subject in need an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some embodiments, the CNS-related disorders are 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, affective disorders (including depression (e.g., postpartum depression, bipolar disorder, dysthymia, suicide), schizophrenia or other psychosis (including affective schizophrenia), sleep disorders (including insomnia), substance-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations in the Shank proteome (e.g., Shank3)), neurodevelopmental disorders (including Rett syndrome, tuberous sclerosis, etc.). Complex), multiple sclerosis, sterol synthesis disorders, pain (including acute and chronic pain; headaches, e.g., migraines), encephalopathy secondary to medical conditions (including hepatic encephalopathy and anti-NMDA receptor encephalitis), seizures (including status epilepticus and monogenic forms of epilepsy such as Dravet disease), stroke, traumatic brain injury, movement disorders (including Huntington's disease and Parkinson's disease), visual impairment, hearing loss, or tinnitus.

[0198] In some embodiments, the condition is Huntington's disease. In some embodiments, the condition is Parkinson's disease. In some embodiments, the condition is an inflammatory disease (e.g., lupus).

[0199] In some implementations, the condition is a sterol synthesis disorder.

[0200] In some embodiments, the condition is Smith-Lemli-Opitz Syndrome (SLOS). In some embodiments, the condition is desmosterolosis. In some embodiments, the condition is hypersitosterolemia. In some embodiments, the condition is cerebral tendon xanthomatosis (CTX). In some embodiments, the condition is mevalonate kinase deficiency (MKD). In some embodiments, the condition is SC4MOL gene mutation (SMO deficiency). In some embodiments, the condition is Niemann-Pick disease. In some embodiments, the condition is autism spectrum disorder (ASD). In some embodiments, the condition is associated with phenylketonuria.

[0201] Other objects and advantages will become apparent to those skilled in the art in light of the following detailed description of the invention, embodiments, and claims.

[0202] definition

[0203] Chemical definition

[0204] The following describes the definitions of specific functional groups and chemical terms in more detail. Chemical elements are identified according to the periodic table, CAS edition, Handbook of Chemistry and Physics, 75th edition, inside cover, and specific functional groups are generally defined as described therein. Additionally, the general principles of organic chemistry, as well as specific functional groups and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0205] Isomers can be separated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (Ellie Liel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The invention also includes compounds described herein as single isomers substantially free of other isomers, or as mixtures of various isomers.

[0206] The term “enantiomer excess” (“ee”) or “% enantiomer excess” (“%ee”) of a composition refers to an excess of one enantiomer relative to another enantiomer present in the composition. For example, a composition may contain 90% of one enantiomer, such as the S enantiomer, and 10% of another enantiomer, namely the R enantiomer.

[0207] ee = (90-10) / 100 = 80%.

[0208] Therefore, a composition containing 90% of one enantiomer and 10% of the other enantiomer has an enantiomer excess of 80%.

[0209] The term "diastereomer excess" ("de") or "% diastereomer excess" ("%de") of a composition refers to an excess of one diastereomer relative to one or more different diastereomers present in the composition. For example, a composition may contain 90% of one diastereomer and 10% of one or more different diastereomers.

[0210] de = (90-10) / 100 = 80%.

[0211] Therefore, a composition containing 90% of one diastereomer and 10% of one or more different diastereomers has an 80% diastereomer excess.

[0212] When listing a range of values, the intention is to include every value within that range and its subranges. For example, "C 1–6"Alkyl" is intended to include C1, C2, C3, C4, C5, C6, C 1–6 C 1–5 C 1–4 C 1–3 C 1–2 C 2–6 C 2–5 C 2–4 C 2–3 C 3–6 C 3–5 C 3–4 C 4–6 C 4–5 and C 5–6 alkyl.

[0213] The following terms are intended to have the meanings set forth below and are used to understand the description and intended scope of the invention. When describing the invention, it may include compounds, pharmaceutical compositions containing these compounds, and methods of using these compounds and compositions, and unless otherwise stated, the following terms (if present) have the following meanings. It should also be understood that, when described herein, any portion defined below may be substituted with various substituents, and the respective definitions are intended to include such substituted portions within their scope, as described below. Unless otherwise stated, the term “substituted” is defined as follows. It should be further understood that, when used herein, the terms “group” and “part” are considered interchangeable. The articles “a” and “an” are used herein to refer to one or more (i.e., at least one) grammatical object of the article. For example, “an analogue” means one or more analogues.

[0214] "Aliphatic" refers to alkyl, alkenyl, ynyl or carbocyclic groups as defined in this article.

[0215] "alkyl" refers to a group consisting of a straight-chain or branched saturated hydrocarbon group having 1-20 carbon atoms ("C"). 1–20 Alkyl group). In some embodiments, the alkyl group has 1-12 carbon atoms (“C12”). 1–12 Alkyl group). In some embodiments, the alkyl group has 1-10 carbon atoms (“C10”). 1–10 Alkyl group). In some embodiments, the alkyl group has 1-9 carbon atoms (“C10”). 1–9 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1-8 carbon atoms (“C”). 1–8 Alkyl group). In some embodiments, the alkyl group has 1-7 carbon atoms (“C17”). 1–7 Alkyl group). In some embodiments, the alkyl group has 1-6 carbon atoms (“C6”). 1–6 Alkyl group (also referred to herein as "lower alkyl group"). In some embodiments, the alkyl group has 1-5 carbon atoms ("C50"). 1–5Alkyl group). In some embodiments, the alkyl group has 1-4 carbon atoms (“C14”). 1–4 Alkyl group). In some embodiments, the alkyl group has 1-3 carbon atoms (“C13”). 1–3 Alkyl group). In some embodiments, the alkyl group has 1-2 carbon atoms (“C12”). 1– 2. Alkyl group (“C1 alkyl”). In some embodiments, the alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, the alkyl group has 2-6 carbon atoms (“C1 alkyl”). 2–6 Alkyl group). C 1–6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). Other examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc. Unless otherwise stated, each example of an alkyl group is independently and optionally substituted, i.e., unsubstituted (“unsubstituted alkyl”) or substituted with one or more substituents (“substituted alkyl”); for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In some embodiments, the alkyl group is an unsubstituted C1. 1–10 Alkyl group (e.g., –CH3). In some embodiments, the alkyl group is a substituted C-molecule. 1–10 Alkyl. Common alkyl abbreviations include Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3) or i-Bu(-CH2CH(CH3)2).

[0216] "Alkylene" refers to an alkyl group in which two hydrogen atoms have been removed to provide a divalent group, and it may be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), and hexylene (-CH2CH2CH2CH2CH2CH2-). Exemplary substituted alkylene groups, such as those 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-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc. When a range or number of carbons is provided for a particular alkylene group, it should be understood that the range or number refers to the range or number of carbons in a straight-chain divalent carbon chain. Alkylene groups may be substituted or unsubstituted with one or more substituents as described herein.

[0217] "Alkenyl" refers to a group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) ("C 2–20 The alkenyl group is a straight-chain or branched hydrocarbon group. In some embodiments, the alkenyl group does not contain any triple bonds. In some embodiments, the alkenyl group has 2-10 carbon atoms (“C10”). 2–10 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2-9 carbon atoms (“C”). 2–9 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2-8 carbon atoms (“C”). 2–8 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2-7 carbon atoms (“C”). 2–7 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2-6 carbon atoms (“C”). 2–6 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2-5 carbon atoms (“C”). 2–5 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2-4 carbon atoms (“C”). 2–4 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2-3 carbon atoms (“C”). 2–3The alkenyl group (“C2-alkenyl”) has two carbon atoms in some embodiments. The one or more carbon-carbon double bonds can be internal (e.g., in a 2-butenyl group) or terminal (e.g., in a 1-butenyl group). 2–4 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. 2–6 Examples of alkenyl groups include the aforementioned C... 2–4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Other examples of alkenyl groups include heptenyl (C7), octenyl (C8), octetrinyl (C8), etc. Unless otherwise stated, each example of an alkenyl group is independently and optionally substituted, i.e., unsubstituted (“unsubstituted alkenyl”) or substituted with one or more substituents (“substituted alkenyl”), for example, 1-5 substituents, 1-3 substituents, or 1 substituent. In some embodiments, the alkenyl group is an unsubstituted C10. 2–10 Alkenyl group. In some embodiments, the alkenyl group is a substituted C group. 2–10 Alkenyl group.

[0218] "Alkyne" refers to a straight-chain or branched hydrocarbon group having 2-20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) ("C 2–20 The alkynyl group (“Alynyl”) is present in some embodiments. In some embodiments, the alkynyl group contains no double bonds. In some embodiments, the alkynyl group has 2-10 carbon atoms (“C”). 2–10 The alkynyl group (“Alynyl”) is present in some embodiments. In some implementations, the alkynyl group has 2-9 carbon atoms (“C”). 2–9 The alkynyl group (“Alynyl”) is present in some embodiments. In some implementations, the alkynyl group has 2-8 carbon atoms (“C”). 2–8 The alkynyl group (“Alynyl”) is present in some embodiments. In some implementations, the alkynyl group has 2-7 carbon atoms (“C”). 2–7 The alkynyl group (“Alynyl”) is present in some embodiments. In some implementations, the alkynyl group has 2-6 carbon atoms (“C”). 2–6 The alkynyl group (“Alynyl”) is present in some embodiments. In some implementations, the alkynyl group has 2-5 carbon atoms (“C”). 2–5 The alkynyl group (“Alynyl”) is present in some embodiments. In some implementations, the alkynyl group has 2-4 carbon atoms (“C”). 2–4 The alkynyl group (“Alynyl”) is present in some embodiments. In some implementations, the alkynyl group has 2-3 carbon atoms (“C”). 2–3 The alkynyl group (“C2-alkynyl”) is used in some embodiments. The one or more carbon-carbon triple bonds can be internal (e.g., in 2-butyne) or terminal (e.g., in 1-butyne). 2–4Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), etc. 2–6 Examples of alkenyl groups include the aforementioned C... 2–4 The alkynyl group includes pentynyl (C5), hexynyl (C6), etc. Other examples of alkynyl groups include heptynyl (C7), octyynyl (C8), etc. Unless otherwise stated, each example of an alkynyl group is independently optionally substituted, i.e., unsubstituted (“unsubstituted alkynyl”) or substituted with one or more substituents (substituted alkynyl); for example, 1-5 substituents, 1-3 substituents, or 1 substituent. In some embodiments, the alkynyl group is an unsubstituted C5 group. 2–10 Alkyne group. In some embodiments, the alkynyl group is a substituted C group. 2–10 Alkyne group.

[0219] As used herein, the term "heteroalkyl" refers to an alkyl group as defined herein, whose parent chain further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), wherein one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or one or more heteroatoms are inserted between carbon atoms and the parent molecule, i.e., between connection points. In some embodiments, heteroalkyl refers to a saturated group ("heteroalkyl") having 1-10 carbon atoms and 1, 2, 3, or 4 heteroatoms. 1–10 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms (“heteroalkyl”). 1–9 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1-8 carbon atoms and 1, 2, 3 or 4 heteroatoms (“heteroalkyl”). 1–8 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1-7 carbon atoms and 1, 2, 3 or 4 heteroatoms (“heteroalkyl”). 1–7 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a group having 1-6 carbon atoms and 1, 2 or 3 heteroatoms (“heteroalkyl”). 1–6 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1-5 carbon atoms and 1 or 2 heteroatoms (“heteroalkyl”). 1–5 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1-4 carbon atoms and 1 or 2 heteroatoms (“heteroalkyl”). 1–4 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1-3 carbon atoms and 1 heteroatom (“heteroalkyl”). 1–3 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1-2 carbon atoms and 1 heteroatom (“heteroalkyl”). 1–2Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having one carbon atom and one heteroatom (“heteroC1 alkyl”). In some embodiments, the heteroalkyl group is a saturated group having 2-6 carbon atoms and one or two heteroatoms (“heteroC1 alkyl”). 2–6 Alkyl group (“Alkyl”). Unless otherwise stated, each example of a heteroalkyl group is independently unsubstituted (“unsubstituted heteroalkyl”) or substituted with one or more substituents (“substituted heteroalkyl”). In some embodiments, the heteroalkyl group is an unsubstituted heteroalkyl group. 1–10 Alkyl group. In some embodiments, the heteroalkyl group is a substituted heteroC. 1–10 alkyl.

[0220] "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system that provides 6–14 ring carbon atoms and zero heteroatoms in the aromatic ring system (e.g., enjoying 6, 10, or 14 π electrons in the ring array). 6–14 Aryl group (“C6 aryl”). In some embodiments, the aryl group has six ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has ten ring carbon atoms (“C6 aryl”). 10 Aryl; for example, naphthyl (e.g., 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen ring carbon atoms (“C”). 14 "Aryl"; for example, anthracene. "Aryl" also includes ring systems in which the aromatic ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the radical or linker is on the aryl ring, and in this case, the number of carbon atoms continues to represent the number of carbon atoms in the aromatic ring system. Typical aryl groups include, but are not limited to, those derived from: aceanthrylene, acenaphthene, acephenanthrylene, anthracene, azurite, benzene, etc. Hexaphene, fluoranthene, fluorene, hexaphene, hexalene, asymmetric indole, symmetric indole, indole, naphthalene, octacene, octaphene, octalene, ovalene, pentacene, pentaphene, pentacyclopentadiene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. In particular, aryl groups include phenyl, naphthyl, indole, and tetrahydronaphthyl. Unless otherwise stated, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (“unsubstituted aryl”) or substituted with one or more substituents (“substituted aryl”). In some embodiments, the aryl group is an unsubstituted C 6–14 Aryl group. In some embodiments, the aryl group is a substituted C-group. 6–14 Aryl.

[0221] In some embodiments, the aryl group is substituted by one or more groups selected from the following: halogen, C1-C8 alkyl, C1-C8 haloalkyl, cyano, hydroxyl, C1-C8 alkoxy, and amino.

[0222] Representative examples of substituted aryl groups include the following:

[0223]

[0224] Where R 56 and R 57 One of them can be hydrogen and R 56 and R 57 At least one of them is independently selected from C1-C8 alkyl, C1-C8 haloalkyl, 4-10 membered heterocyclic, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 NR 58 SOR 59 NR 58 SO2R 59 COO alkyl, COO aryl, CONR 58 R 59 CONR 58 OR 59 NR 58 R59 SO2NR 58 R 59 S-alkyl, SO-alkyl, SO2-alkyl, S-aryl, SO-aryl, SO2-aryl; or R 56 and R 57 They can be linked to form cyclic rings (saturated or unsaturated) of 5 to 8 atoms, which optionally contain one or more heteroatoms selected from N, O or S. R 60 and R 61 Independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl, substituted C6-C 10 Aryl, 5-10 heteroaryl or substituted 5-10 heteroaryl.

[0225] "Fused aryl" refers to an aryl group in which two of its ring carbons are shared with a second aryl or heteroaryl ring, or with a carbocyclic or heterocyclic ring.

[0226] "Heteroaryl" refers to a group in a 5-10 member monocyclic or bicyclic 4n+2 aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms (e.g., having 6 or 10 π electrons shared in a cyclic array), wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 member heteroaryl"). In heteroaryls containing one or more nitrogen atoms, the linkage can be a carbon atom or a nitrogen atom, provided the valence allows it. A heteroaryl bicyclic system may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the linkage is on the heteroaryl ring, and in this case, the number of ring members continues to represent the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups, wherein the linkage is on the aryl or heteroaryl ring, and in this case, the number of ring members represents the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups, in which one ring does not contain heteroatoms (e.g., indole, quinolinyl, carbazolyl, etc.), and the bonding point can be on either ring, i.e., a ring with heteroatoms (e.g., 2-indole) or a ring without heteroatoms (e.g., 5-indole).

[0227] In some embodiments, the heteroaryl group is a 5-10 cyclic aromatic ring system provided in an aromatic ring system, having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 cyclic heteroaryl”). In some embodiments, the heteroaryl group is a 5-8 cyclic aromatic ring system provided in an aromatic ring system, having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 cyclic heteroaryl”). In some embodiments, the heteroaryl group is a 5-6 cyclic aromatic ring system provided in an aromatic ring system, having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 cyclic heteroaryl”). In some embodiments, the 5-6 cyclic heteroaryl group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 cyclic heteroaryl group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6-membered heteroaryl group has one cyclic heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise stated, each instance of the heteroaryl group is optionally substituted independently, i.e., unsubstituted (“unsubstituted heteroaryl”) or substituted with one or more substituents (“substituted heteroaryl”). In some embodiments, the heteroaryl group is an unsubstituted 5–14-membered heteroaryl group. In some embodiments, the heteroaryl group is a substituted 5–14-membered heteroaryl group.

[0228] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrroleyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetraazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azirheptatrienyl, oxadiaztatrienyl, and thioheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazole, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthidyl, piperidinyl, quinolinyl, isoquinolinyl, cenolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0229] Representative examples of heteroaryl groups include the following:

[0230]

[0231] Each Z is selected from carbonyl, N, NR 65 O and S; and R 65 Independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl compounds.

[0232] "Carbocyclic" or "carbocyclic" refers to a non-aromatic ring system having 3 to 10 ring carbon atoms ("C"). 3–10 A group consisting of a carbocyclic group (“C”) and a non-aromatic cyclic hydrocarbon group with 0 heteroatoms. In some embodiments, the carbocyclic group has 3 to 8 cyclic carbon atoms (“C”). 3–8 (Carbocyclic group). In some embodiments, the carbocyclic group has 3 to 6 cyclic carbon atoms (“C”). 3–6 (Carbocyclic group). In some embodiments, the carbocyclic group has 3 to 6 cyclic carbon atoms (“C”). 3–6 (Carbocyclic group). In some embodiments, the carbocyclic group has 5 to 10 cyclic carbon atoms (“C”). 5–10 (Carbocyclic group"). An example C 3–6 Carbocyclic 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). An example is C... 3–8 Carbocyclic groups include, but are not limited to, the C groups mentioned above. 3–6 Carbocyclic groups, including cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), etc. An example C 3–10 Carbocyclic groups include, but are not limited to, the C groups mentioned above. 3–8 Carbocyclic groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ), spiro[4.5]decyl(C 10As illustrated in the foregoing embodiments, in some embodiments, the carbocyclic group is a monocyclic (“monocyclic carbocyclic”) or contains a fused, bridged, or spirocyclic system, such as a bicyclic system (“bicyclic carbocyclic”), and may be saturated or may be partially unsaturated. “Carbocyclic” also includes ring systems in which the carbocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the connection point is on the carbocyclic ring, and in this case, the number of carbons continues to represent the number of carbons in the carbocyclic system. Unless otherwise stated, each instance of a carbocyclic group is optionally independently substituted, i.e., unsubstituted (“unsubstituted carbocyclic”) or substituted with one or more substituents (“substituted carbocyclic”). In some embodiments, the carbocyclic group is an unsubstituted C 3–10 Carbocyclic group. In some embodiments, the carbocyclic group is a substituted C 3–10 Carbon cyclic group.

[0233] In some implementations, "carbocyclic group" is a monocyclic saturated carbocyclic group ("C") having 3 to 10 ring carbon atoms. 3–10 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 8 cyclic carbon atoms (“C”). 3–8 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 6 cyclic carbon atoms (“C”). 3–6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 6 cyclic carbon atoms (“C”). 5–6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 10 cyclic 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 aforementioned C 5–6 Cycloalkyl groups, as well as cyclopropyl (C3) and cyclobutyl (C4). C 3–8 cycloalkyl groups include the aforementioned C 3–6 Cycloalkyl groups, including cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise stated, each instance of a cycloalkyl group is independently unsubstituted (“unsubstituted cycloalkyl”) or substituted with one or more substituents (“substituted cycloalkyl”). In some embodiments, the cycloalkyl group is an unsubstituted C7 group. 3–10 Cycloalkyl. In some embodiments, the cycloalkyl group is a substituted C-type alkyl group. 3–10 Cycloalkyl.

[0234] "Heterocyclic group" or "heterocyclic" refers to a group having a 3- to 10-membered non-aromatic ring system with a ring carbon atom and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (3- to 10-membered heterocyclic groups). In heterocyclic groups containing one or more nitrogen atoms, the linkage can be either carbon or nitrogen atoms, provided that the valence allows it. Heterocyclic groups can be monocyclic ("monocyclic heterocyclic group") or fused, bridged, or spirocyclic systems, such as bicyclic systems ("bicyclic heterocyclic group"), and can be saturated or partially unsaturated. A bicyclic heterocyclic system may contain one or more heteroatoms in one or both rings. "Heterocyclic group" also includes ring systems in which the heterocyclic ring as defined above is fused with one or more carbocyclic groups, wherein the connection point is on the carbocyclic or heterocyclic ring, or includes ring systems in which the heterocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the connection point is on the heterocyclic ring, and in this case, the number of ring members continues to represent the number of ring members in the heterocyclic ring system. Unless otherwise stated, each instance of a heterocyclic group is independently and optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclic group") or substituted with one or more substituents ("substituted heterocyclic group"). In some embodiments, the heterocyclic group is an unsubstituted 3-10 membered heterocyclic group. In some embodiments, the heterocyclic group is a substituted 3-10 membered heterocyclic group.

[0235] In some embodiments, the heterocyclic group is a 5-10 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-8 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-6 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclic group”). In some embodiments, the 5-6 membered heterocyclic group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has one cyclic heteroatom selected from nitrogen, oxygen, and sulfur.

[0236] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirropropyl, oxacyclopropyl, and thiocyclopropyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirrobutyl, oxacyclobutyl, and thiocyclobutyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolidinyl, and pyrrolidin-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thiocyclohexyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithiocyclohexyl, and dioxanyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, [1,3,5]triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxeheptanyl, and thioheptanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxeheptanyl, and thioheptanyl. Exemplary 5-membered heterocyclic groups fused with a C6 aromatic ring (also referred to herein as 5,6-bicyclic heterocycles) include, but are not limited to, dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, etc. Exemplary 6-membered heterocyclic groups fused with aryl rings (also referred to herein as 6,6-bicyclic heterocycles) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0237] "Nitrogen-containing heterocyclic group" refers to a 4- to 7-membered non-aromatic cyclic group containing at least one nitrogen atom, such as, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azacyclic butane, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazine such as N-methylpiperazine. Specific examples include azacyclic butane, piperidinone, and piperazone.

[0238] When used to describe a compound or a group present on a compound, "hetero" means that one or more carbon atoms in the compound or group have been replaced by nitrogen, oxygen, or sulfur heteroatoms. Heteroatoms can be applied to any of the above-mentioned hydrocarbon groups, such as alkyl (e.g., heteroalkyl), cycloalkyl (e.g., heterocyclic), aryl (e.g., heteroaryl), cycloalkenyl (e.g., heterocyclic heteroalkenyl), etc., which have 1 to 5, especially 1 to 3, heteroatoms.

[0239] "Acyl" refers to the group -C(O)R 20 , where R 20 The group is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein. "Alkyl" is an acyl group, wherein R... 20 Acyl groups are groups other than hydrogen. Representative acyl groups include, but are not limited to, 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 heteroaryl groups), –C(O)-(CH2) t (C3-C 10 Cycloalkyl) and –C(O)-(CH2) t (4-10-membered heterocyclic base), where t is an integer from 0 to 4. In some implementations, R 21 It is a C1-C8 alkyl group, which is substituted with halogens or hydroxyl groups; or C3-C 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl, arylalkyl, 5-10 heteroaryl or heteroarylalkyl, each of which is substituted by: unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxyl.

[0240] "Alkoxy" refers to the group –OR 29 , where R 29The alkoxy group can be substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Specific alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Specific alkoxy groups are lower alkoxy groups, i.e., having 1 to 6 carbon atoms. Other specific alkoxy groups have 1 to 4 carbon atoms.

[0241] In some implementation schemes, R 29 It is a group having one or more substituents, for example, 1 to 5 substituents, particularly 1 to 3 substituents, especially a group with 1 substituent, said substituent being selected from amino, substituted amino, C6-C 10 Aryl, aryloxy, carboxyl, cyano, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic groups, halogens, 5-10 membered heteroaryl groups, hydroxyl groups, nitro groups, thioalkoxy groups, thioaryloxy groups, thiols, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2-, and aryl-S(O)2-. Exemplary 'substituted alkoxy' groups include, but are not limited to, O-(CH2). t (C6-C 10 Aryl), –O-(CH2) t (5-10 heteroaryl groups), –O-(CH2) t (C3-C 10 (cycloalkyl) and –O-(CH2) t (4-10 membered heterocyclic groups), where t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl, or heterocyclic group present can be substituted with: unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxyl. Specific exemplary 'substituted alkoxy' groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2.

[0242] "Amino" refers to the group -NH2.

[0243] "Oxide group" refers to –C(=O)–.

[0244] "Substituted amino group" refers to the formula -N(R 38 The amino group of )2, wherein R 38It is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or amino protecting group, wherein R 38 At least one of them is not hydrogen. In some embodiments, each R 38 Independently selected from hydrogen, C1-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic or C3-C 10 Cycloalkyl; or C1-C8 alkyl substituted with halogen or hydroxyl; C3-C8 alkenyl substituted with halogen or hydroxyl; C3-C8 alkynyl substituted with halogen or hydroxyl or -(CH2). t (C6-C 10 Aryl), -(CH2) t (5-10 heteroaryl groups), -(CH2) t (C3-C 10 (cycloalkyl) or -(CH2) t (4-10 membered heterocyclic groups), where t is an integer between 0 and 8, each of which is substituted by: unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; or two R groups. 38 Groups are linked to form alkylene groups.

[0245] Exemplary “substituted amino” groups include, but are not limited to, –NR 39 -C1-C8 alkyl, –NR 39 -(CH2) t (C6-C 10 aryl), –NR 39 -(CH2) t (5-10 grade heteroaryl), –NR 39 -(CH2) t (C3-C 10 cycloalkyl) and –NR 39 -(CH2) t (4-10-membered heterocyclic bases), where t is an integer from 0 to 4, for example, 1 or 2, and each R 39Independently representing H or C1-C8 alkyl; and any alkyl group present may itself be substituted with a halogen, a substituted or unsubstituted amino or hydroxyl group; and any aryl, heteroaryl, cycloalkyl, or heterocyclic group present may itself be substituted with an unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxyl group. For the avoidance of doubt, the term "substituted amino" includes alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino, as defined below. Substituted amino groups include monosubstituted and disubstituted amino groups.

[0246] "Carboxyl group" refers to the group -C(O)OH.

[0247] "Cyano" refers to the group -CN.

[0248] "Halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In some embodiments, the halogen group is fluorine or chlorine.

[0249] "Halogenated alkyl" refers to an alkyl group in which the alkyl group is replaced by one or more halogens. Typical halogenated alkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, tetrafluoroethyl, etc.

[0250] "Hydroxy group" refers to the -OH group.

[0251] "Nitro" refers to the group –NO2.

[0252] "Thioketone" refers to the group =S.

[0253] Alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups as defined herein may be optionally substituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” carbocyclic, “substituted” or “unsubstituted” heterocyclic, “substituted” or “unsubstituted” aryl, or “substituted” or “unsubstituted” heteroaryl). Generally, the term “substituted,” whether or not preceding the term “optionally,” means that at least one hydrogen atom (e.g., a carbon or nitrogen atom) present on the group is substituted by a permitted substituent, such as a substituent that, upon substitution, yields a stable compound, e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reactions. Unless otherwise stated, a “substituted” group has a substituent at one or more substituted positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term "substituted" includes substitution with any of the permitted substituents of an organic compound, any substituent described herein resulting in the formation of a stable compound. This invention contemplates any and all such combinations to obtain a stable compound. For the purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents as described herein, satisfying the valence of the heteroatom and resulting in the formation of a stable moiety.

[0254] Exemplary carbon atom substituents include, but are not limited to, halogens, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, and –OR. aa –ON(R) bb )2、–N(R bb )2、–N(R bb )3 + X – –N(OR) cc )R bb –SH, –SR aa –SSR cc –C(=O)R aa –CO2H, –CHO, –C(OR) cc )2、–CO2R aa –OC(=O)R aa –OCO2R aa –C(=O)N(R) bb )2、–OC(=O)N(R bb )2、–NR bb C(=O)R aa –NR bb CO2R aa –NR bb C(=O)N(R bb)2、–C(=NR bb )R aa 、–C(=NR bb )OR aa 、–OC(=NR bb )R aa 、–OC(=NR bb )OR aa 、–C(=NR bb )N(R bb )2、–OC(=NR bb )N(R bb )2、–NR bb C(=NR bb )N(R bb )2、–C(=O)NR bb SO2R aa 、–NR bb SO2R aa 、–SO2N(R bb )2、–SO2R aa 、–SO2OR aa 、–OSO2R aa 、–S(=O)R aa 、–OS(=O)R aa 、–Si(R aa )3、–OSi(R aa )3–C(=S)N(R bb )2、–C(=O)SR aa 、–C(=S)SR aa 、–SC(=S)SR aa 、–SC(=O)SR aa 、–OC(=O)SR aa 、–SC(=O)OR aa 、–SC(=O)R aa 、–P(=O)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)(NRbb )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 alkenyl, C 2–10 alkynyl group, C 3–10 Carbocyclic groups, 3–14 membered heterocyclic groups, C 6–14 Aryl and 5–14-membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution; or two twin hydrogens on a carbon atom being replaced by groups =O, =S, =NN(R) bb )2、=NNR bb C(=O)R aa =NNR bb C(=O)OR aa =NNR bb S(=O)2R aa =NR bb or = NOR cc replace;

[0255] R aa Each instance is independently selected from C 1–10 Alkyl, C 1–10 Haloalkyl, C 2–10 alkenyl, C 2–10 alkynyl group, C 3–10 Carbocyclic groups, 3–14 membered heterocyclic groups, C 6–14 aryl and 5–14 heteroaryl or two R aa The groups together form a 3–14 membered heterocyclic ring or a 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0256] R bb Each instance is independently selected from hydrogen, –OH, –OR aa –N(R) cc )2、–CN、–C(=O)R aa –C(=O)N(R) cc )2、–CO2R aa –SO2R aa–C(=NR) cc OR aa –C(=NR) cc )N(R cc )2、–SO2N(R cc )2、–SO2R cc –SO2OR cc –SOR aa –C(=S)N(R) cc )2、–C(=O)SR cc –C(=S)SR cc –P(=O)2R aa –P(=O)(R aa )2、–P(=O)2N(R cc )2、–P(=O)(NR cc 2. C 1–10 Alkyl, C 1–10 Haloalkyl, C 2–10 alkenyl, C 2–10 alkynyl group, C 3–10 Carbocyclic groups, 3–14 membered heterocyclic groups, C 6–14 aryl and 5–14 heteroaryl or two R bb The groups together form a 3–14 membered heterocyclic ring or a 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0257] R cc Each instance is independently selected from hydrogen, C 1–10 Alkyl, C 1–10 Haloalkyl, C 2–10 alkenyl, C 2–10 alkynyl group, C 3–10 Carbocyclic groups, 3–14 membered heterocyclic groups, C 6–14 aryl and 5–14 heteroaryl or two R cc The groups together form a 3–14 membered heterocyclic ring or a 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0258] R dd Each instance is independently selected from halogens, –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 ee , –NR ff CO2R ee , –NR ff C(=O)N(R ff )2, –C(=NR ff )OR ee , –OC(=NR ff )R ee , –OC(=NR ff )OR ee , –C(=NR ff )N(R ff )2, –OC(=NR ff )N(R ff )2, –NR ff C(=NR ff )N(R ff )2, –NR ff SO2R ee , –SO2N(R ff )2, –SO2R ee , –SO2OR ee , –OSO2R ee , –S(=O)R ee , –Si(R ee )3, –OSi(R ee )3, –C(=S)N(R ff )2, –C(=O)SR ee , –C(=S)SR ee , –SC(=S)SR ee , –P(=O)2R ee , –P(=O)(R ee )2, –OP(=O)(R ee )2, –OP(=O)(OR ee )2, C 1–6 alkyl, C 1–6 haloalkyl, C 2–6 alkenyl, C2–6 alkynyl group, C 3–10 Carbocyclic groups, 3–10-membered heterocyclic groups, C 6–10 Aryl, 5–10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution or two twins R dd Substituents can be combined to form =O or =S;

[0259] R ee Each instance is independently selected from C 1–6 Alkyl, C 1–6 Haloalkyl, C 2–6 alkenyl, C 2–6 alkynyl group, C 3–10 carbonyl group, C 6–10 Aryl, 3–10-membered heterocyclic and 3–10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl group is independently bounded by 0, 1, 2, 3, 4 or 5 R groups. gg Group substitution;

[0260] R ff Each instance is independently selected from hydrogen, C 1–6 Alkyl, C 1–6 Haloalkyl, C 2–6 alkenyl, C 2–6 alkynyl group, C 3–10 Carbocyclic groups, 3–10-membered heterocyclic groups, C 6–10 aryl and 5–10 heteroaryl or two R ff The groups together form a 3–14 membered heterocyclic ring or a 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution; and

[0261] R gg Each instance is independently a halogen, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, –OC 1–6 Alkyl, –ON(C 1–6 Alkyl)2、–N(C 1–6 Alkyl)2、–N(C 1–6 Alkyl)3 + X – –NH(C 1–6 Alkyl)2 + X – –NH2(C 1–6 alkyl) + X – –NH3 + X – –N(OC)1–6 Alkyl)(C 1–6 Alkyl), –N(OH)(C 1–6 Alkyl groups, –NH(OH), –SH, –SC 1–6 Alkyl, –SS(C 1–6 Alkyl), –C(=O)(C 1–6 Alkyl group), –CO2H, –CO2(C 1–6 Alkyl), –OC (=O)(C 1–6 Alkyl), –OCO2(C 1–6 Alkyl groups, –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 groups), –NHC(=O)NH2, –C(=NH)O(C 1–6 Alkyl), –OC (=NH)(C 1–6 Alkyl group), –OC (=NH)OC 1–6 Alkyl group, –C(=NH)N(C 1–6 Alkyl)2、–C(=NH)NH(C 1–6 Alkyl groups, –C(=NH)NH2, –OC(=NH)N(C 1–6 Alkyl)2、–OC(NH)NH(C 1–6 Alkyl groups), –OC(NH)NH2, –NHC(NH)N(C 1–6 Alkyl)2, –NHC(=NH)NH2, –NHSO2(C 1–6 Alkyl), –SO2N(C 1–6 Alkyl)2、–SO2NH(C 1–6 Alkyl groups, –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 1–6Alkyl), –C(=S)SC 1–6 Alkyl, –SC (=S)SC 1–6 Alkyl group, –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 alkenyl, C 2–6 alkynyl group, C 3–10 carbonyl group, C 6–10 aryl, 3–10-membered heterocyclic, 5–10-membered heteroaryl; or two twin R gg Substituents can together form =O or =S; where X – To counteract ions.

[0262] "Counterions" or "anionic counterions" are negatively charged groups that associate with a quaternary amino group of a cationic group to maintain electroneutrality. Exemplary counterions include halide ions (e.g., F-, Cl-, Br-, I-), NO3-, etc. – ClO4 – OH – H2PO4 – HSO4 – SO4 -2 Sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonate-5-sulfonate, ethane-1-sulfonate-2-sulfonate, etc.) and carboxylate ions (e.g., acetate, ethanoate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0263] When the valence allows, the nitrogen atom can be substituted or unsubstituted, and includes primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen substituents include, but are not limited to, 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 alkenyl, C 2–10 alkynyl group, C 3–10 Carbocyclic groups, 3–14 membered heterocyclic groups, C 6–14 aryl and 5–14-membered heteroaryl groups or two R groups attached to the nitrogen atom cc The groups together form a 3-14 membered heterocyclic ring or a 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution and R aa R bb R cc and R dd As defined above.

[0264] These and other exemplary substituents are described in more detail in the detailed description of the invention, embodiments, and claims. The invention is not in any way limited to the substituents exemplified above.

[0265] Other definitions

[0266] The term "pharmaceutically acceptable salt" refers to those salts that, within reasonable medical judgment, are suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. described pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1–19. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and inorganic and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed with amino groups of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or salts formed by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, gluconate, glyceryl phosphate, gluconate, hemisulfate, heptaate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pyrate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, p-valerate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Pharmaceutically acceptable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1–4 Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0267] The term "subject" considered for administration includes, but is not limited to, humans (i.e., men or women of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, such as mammals, such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0268] Disease, obstacle, and symptom are used interchangeably in this article.

[0269] As used herein, and unless otherwise stated, the term “treatment” refers to an effect that occurs when a subject has a particular disease, disorder, or condition, which reduces the severity of said disease, disorder, or condition or delays or slows the progression of said disease, disorder, or condition (“therapeutic treatment”), and also to an effect that occurs before the subject begins to have a particular disease, disorder, or condition (“preventive treatment”).

[0270] Generally, the “effective amount” of a compound refers to the amount sufficient to elicit the desired biological response. As will be understood by those skilled in the art, the effective amount of the compounds of the present invention can vary depending on the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the route of administration, and the age, health, and condition of the subject. Effective amounts include both therapeutic and prophylactic treatments.

[0271] As used herein, and unless otherwise stated, a "therapeuticly effective amount" of a compound is an amount sufficient to provide therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with said disease, disorder, or condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other therapies, that provides therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeuticly effective amount" may include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0272] As used herein, and unless otherwise stated, a "preventively effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or to prevent one or more symptoms associated with a disease, disorder, or condition, or to prevent its recurrence. A preventively effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other agents, that provides a preventive benefit in the prevention of a disease, disorder, or condition. The term "preventively effective amount" may also include amounts that improve overall prevention or enhance the preventive efficacy of another preventive agent.

[0273] Detailed description of specific embodiments of the present invention

[0274] As generally described herein, the present invention provides substituted oxosterols for the prevention and / or treatment of a variety of diseases, including but not limited to NMDA-mediated diseases.

[0275] compound

[0276] In one respect, this paper provides compounds of formula (A):

[0277]

[0278] Or its pharmaceutically acceptable salt, wherein:

[0279] R 1A and R 1B Each of the following is independently hydrogen, substituted or unsubstituted alkyl, carbocyclic, heterocyclic, aryl or heteroaryl, or R. 1A and R 1B Together with the carbon atoms they are attached to, they form 3-8 membered rings;

[0280] n is 1 or 2;

[0281] R 2A and R 2B Each independently represents hydrogen, halogen, –OR C alkyl, alkenyl, alkynyl, aryl or heteroaryl, wherein R C It is hydrogen or alkyl or R 2A and R 2B Together with the carbon atoms they are attached to, they form oxo groups, where R 2A and R 2B They are not both hydrogen;

[0282] R 3 It can be hydrogen, alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group;

[0283] R 4 It is either non-existent or is hydrogen; and

[0284] Represents a single bond or a double bond, where when one When it is a double bond, then the other one... For a single bond; when two When all bonds are single bonds, then R 4 For hydrogen; and when one When it is a double bond, R 4 It does not exist.

[0285] In some implementations, n is 1. In other implementations, n is 2.

[0286] In some implementations, when R 1AR 3 and R 4 For hydrogen and R 1B When it is an unsubstituted isopropyl group, then R 2A and R 2B They do not form oxo groups together with the carbon atoms they are attached to; and when R 4 It does not exist, R 3 For hydrogen and R 1A and R 1B When it is –CH3, then R 2A Not for –CH3 and R 2B Not –OH.

[0287] In some implementations, when R 4 It does not exist, R 2A For –OH, R 2B For hydrogen or –CF3 and R 1A and R 1B When it is –CH3, then R 3 Not hydrogen; and when R 1A and R 1B For –CH3 and R 3 When it is hydrogen, then R 2A and R 2B They do not form oxo groups together with the carbon atoms they are attached to.

[0288] In some embodiments, the compound of formula (A) is a compound of formula (AI):

[0289]

[0290] In some embodiments, compound (A) is compound (A-II):

[0291]

[0292] In some embodiments, compound (A) is a compound of formula (A-III):

[0293]

[0294] In some embodiments, the compound of formula (A) is a compound of formula (A-IV), (AV), or (A-VI):

[0295]

[0296] Where R 2C Hydrogen or alkyl and R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group.

[0297] In some embodiments, the compound of formula (A) is a compound of formula (A-VII), (A-VIII), or (A-IX):

[0298] Where R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group.

[0299] In some embodiments, the compound of formula (A) is a compound of formula (AX):

[0300]

[0301] Where R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group.

[0302] In some embodiments, the compound of formula (A) is a compound of formula (A-XII).

[0303]

[0304] Where R' is an alkyl group or –OR A , where R A It is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5 or 6; and m is 0, 1, 2 or 3.

[0305] In some implementation schemes, R 4 It does not exist, R 2A and R 2B One of them is –OH and R 3 It is not hydrogen.

[0306] In some implementation schemes, R 1A and R 1B Each is independently an unsubstituted or substituted alkyl group (e.g., haloalkyl, alkoxyalkyl, –CH3, –CH2CH3, –CH(CH3)2, –CF3 or –CH2OCH3).

[0307] In other implementations, R 1A and R 1B Each is independently a substituted alkyl group (e.g., a haloalkyl group). In some embodiments, R 1A and R 1B It is an alkyl group (e.g., unsubstituted or substituted alkyl groups (e.g., –CH3)). In some embodiments, R 1A and R 1B It is –CH3.

[0308] In some respects, R 1AIt can be –CF3 or –CH2OCH3.

[0309] In other respects, R 1A For hydrogen and R 1B It can be alkyl, carbocyclic, heterocyclic, aryl, or heteroaryl.

[0310] In some implementation schemes, R 1A and R 1B Together with the carbon atoms they are attached to, they form 3-8 membered rings.

[0311] In some respects, R 1A For substituted alkyl or unsubstituted C2-C6 alkyl and R 1B It is a substituted or unsubstituted C1-C6 alkyl group.

[0312] In some implementation schemes, R 2A and R 2B Each is independently an alkyl group (e.g., substituted or unsubstituted alkyl). In some respects, R 2A and R 2B Each is independently represented by –F.

[0313] In other implementations, R 2A and R 2B For –CH3 and R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group. In some other embodiments, R 2A and R 2B Each independently consists of hydrogen and R 3 It is an alkyl group (e.g., substituted or unsubstituted alkyl).

[0314] In some implementations, R 3 It is an alkyl (e.g., substituted or unsubstituted alkyl), alkenyl, ynyl, or –OR A , where R A It is an alkyl group. In other embodiments, R 3 It is an alkyl group (e.g., substituted or unsubstituted alkyl).

[0315] In one respect, this paper provides compounds of formula (B):

[0316]

[0317] Or its pharmaceutically acceptable salt, wherein:

[0318] R 1A and R 1B Each of the following is independently hydrogen, substituted or unsubstituted alkyl, carbocyclic, heterocyclic, aryl or heteroaryl, or R. 1A and R1B Together with the carbon atoms they are attached to, they form 3-8 membered rings;

[0319] n is 1 or 2;

[0320] R 2A and R 2B Each independently represents hydrogen, halogen, –OR C alkyl, alkenyl, alkynyl, aryl or heteroaryl, wherein R C It is hydrogen or alkyl or R 2A and R 2B Together with the carbon atoms they are attached to, they form oxo groups, where R 2A and R 2B They are not both hydrogen;

[0321] R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group;

[0322] R 4 It is either non-existent or is hydrogen; and

[0323] Represents a single bond or a double bond, where when one When it is a double bond, then the other one... For a single bond; when two When all bonds are single bonds, then R 4 For hydrogen; and when one When it is a double bond, R 4 It does not exist.

[0324] In some implementations, n is 1. In other implementations, n is 2.

[0325] In some embodiments, the compound of formula (B) is a compound of formula (BI):

[0326]

[0327] In some embodiments, the compound of formula (B) is a compound of formula (B-II):

[0328]

[0329] In some embodiments, the compound of formula (B) is a compound of formula (B-III):

[0330]

[0331] In some embodiments, the compound of formula (B) is a compound of formula (B-IV), (BV), or (B-VI):

[0332]

[0333]

[0334] Where R 2C Hydrogen or alkyl and R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group. In some embodiments, the compound of formula (B) is a compound of formula (B-VII), (B-VIII), or (B-IX):

[0335] Where R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group.

[0336] In some embodiments, the compound of formula (B) is a compound of formula (BX):

[0337]

[0338] Where R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group.

[0339] In some embodiments, the compound of formula (B) is a compound of formula (B-XII).

[0340]

[0341] Where R' is an alkyl group or –OR A , where R A It is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5 or 6; and m is 0, 1, 2 or 3.

[0342] In some implementation schemes, R 1A and R 1B Each is independently an unsubstituted or substituted alkyl group (e.g., haloalkyl, alkoxyalkyl, –CH3, –CH2CH3, –CH(CH3)2, –CF3 or –CH2OCH3).

[0343] In other implementations, R 1A and R 1B Each is independently a substituted alkyl group (e.g., a haloalkyl group). In some embodiments, R 1A and R 1B It is an alkyl group (e.g., unsubstituted or substituted alkyl groups (e.g., –CH3)). In some embodiments, R1A and R 1B It is –CH3.

[0344] In some respects, R 1A It can be –CF3 or –CH2OCH3.

[0345] In other respects, R 1A For hydrogen and R 1B It can be alkyl, carbocyclic, heterocyclic, aryl, or heteroaryl.

[0346] In some implementation schemes, R 1A and R 1B Together with the carbon atoms they are attached to, they form 3-8 membered rings.

[0347] In some respects, R 1A For substituted alkyl or unsubstituted C2-C6 alkyl and R 1B It is a substituted or unsubstituted C1-C6 alkyl group.

[0348] In some implementation schemes, R 2A and R 2B Each is independently an alkyl group (e.g., substituted or unsubstituted alkyl). In some respects, R 2A and R 2B Each is independently represented by –F.

[0349] In other implementations, R 2A and R 2B For –CH3 and R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group. In some other embodiments, R 2A and R 2B Each independently consists of hydrogen and R 3 It is an alkyl group (e.g., substituted or unsubstituted alkyl).

[0350] In some implementations, R 3 It is an alkyl (e.g., substituted or unsubstituted alkyl), alkenyl, ynyl, or –OR A , where R A It is an alkyl group. In other embodiments, R 3 It is an alkyl group (e.g., substituted or unsubstituted alkyl).

[0351] In one respect, this paper provides compounds of formula (I):

[0352]

[0353] Or its pharmaceutically acceptable salt, wherein:

[0354] R1A and R 1B Each of the following is independently hydrogen, substituted or unsubstituted alkyl, carbocyclic, heterocyclic, aryl or heteroaryl, or R. 1A and R 1B Together with the carbon atoms they are attached to, they form 3-8 membered rings; R 2A and R 2B Each independently represents hydrogen, halogen, –OR C alkyl, alkenyl, alkynyl, aryl or heteroaryl, wherein R C It is hydrogen or alkyl or R 2A and R 2B Together with the carbon atoms they are attached to, they form oxo groups, where R 2A and R 2B Not both hydrogen; R 3 It can be hydrogen, alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group; R 4 It is either non-existent or is hydrogen; and Represents a single bond or a double bond, where when one When it is a double bond, then the other one... For a single bond; when two When all bonds are single bonds, then R 4 For hydrogen; and when one When it is a double bond, R 4 It does not exist; where R is not present. 1A R 3 and R 4 For hydrogen and R 1B When it is an unsubstituted isopropyl group, then R 2A and R 2B They do not form oxo groups together with the carbon atoms they are attached to; and when R 4 It does not exist, R 3 For hydrogen and R 1A and R 1B When it is –CH3, then R 2A Not for –CH3 and R 2B Not –OH.

[0355] In some implementation schemes, R 1A R 3 and R 4 For hydrogen, R 1B For unsubstituted isopropyl and R 2A and R 2B They do not form oxo groups together with the carbon atoms they are attached to.

[0356] In some implementation schemes, R 4 It does not exist, R 3 For hydrogen, R 1A and R1B For –CH3, R 2A Not for –CH3 and R 2B Not –OH.

[0357] In some embodiments, the compound of formula (I) is a compound of formula (IA):

[0358]

[0359] In some embodiments, the compound of formula (I) is a compound of formula (IB):

[0360]

[0361] In some embodiments, the compound of formula (I) is a compound of formula (IC):

[0362]

[0363] In some embodiments, the compound of formula (I) is a compound of formula (IE), (IF), or (IG):

[0364]

[0365] Where R 2C Hydrogen or alkyl and R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group.

[0366] In some embodiments, the compound of formula (I) is a compound of formula (IH), (II), or (IJ):

[0367]

[0368] Where R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group.

[0369] In some embodiments, the compound of formula (I) is a compound of formula (IK):

[0370]

[0371] Where R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group.

[0372] In some embodiments, the compound of formula (I) is a compound of formula (IM):

[0373]

[0374] Where R' is an alkyl group or –OR A , where R A It is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5 or 6; and m is 0, 1, 2 or 3.

[0375] In some implementation schemes, R 1A and R 1B Each is independently an unsubstituted or substituted alkyl group (e.g., substituted or unsubstituted –CH3, –CH2CH3, –CH(CH3)2, –CF3 or –CH2OCH3).

[0376] In some implementation schemes, R 1A and R 1B Each is independently a substituted alkyl group (e.g., a haloalkyl group).

[0377] In some implementation schemes, R 1A It can be –CF3 or –CH2OCH3.

[0378] In some implementation schemes, R 1A and R 1B It is an alkyl group (e.g., unsubstituted or substituted alkyl groups (e.g., –CH3)).

[0379] In some implementation schemes, R 1A and R 1B It is –CH3.

[0380] In some implementation schemes, R 1A and R 1B Together with the carbon atoms they are attached to, they form 3-8 membered rings.

[0381] In some implementation schemes, R 1A For hydrogen and R 1B It can be alkyl, carbocyclic, heterocyclic, aryl, or heteroaryl.

[0382] In some implementation schemes, R 1A For substituted alkyl or unsubstituted C2-C6 alkyl and R 1B It is a substituted or unsubstituted C1-C6 alkyl group.

[0383] In some implementation schemes, R 2A and R 2B Each is an alkyl group (e.g., substituted or unsubstituted alkyl groups).

[0384] In some implementation schemes, R 2A and R 2B Each is independently represented by –F.

[0385] In some implementation schemes, R 2A and R 2B For –CH3 and R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group.

[0386] In some implementation schemes, R 2A and R 2B For –F.

[0387] In some implementation schemes, R 3 It is an alkyl (e.g., substituted or unsubstituted alkyl), alkenyl, ynyl, or –OR A , where R A It is an alkyl group.

[0388] In some implementation schemes, R 3 It is an alkyl group (e.g., substituted or unsubstituted alkyl).

[0389] In some implementation schemes, R 2A and R 2B Each independently consists of hydrogen and R 3 It is an alkyl group (e.g., substituted or unsubstituted alkyl).

[0390] In one respect, this paper provides compounds of formula (II):

[0391]

[0392] Or its pharmaceutically acceptable salt, wherein:

[0393] R 1A and R 1B Each of the following is independently hydrogen, substituted or unsubstituted alkyl, carbocyclic, heterocyclic, aryl or heteroaryl, or R. 1A and R 1B Together with the carbon atoms they are attached to, they form 3-8 membered rings;

[0394] R 2A and R 2B Each independently represents hydrogen, halogen, –OR C alkyl, alkenyl, alkynyl, aryl or heteroaryl, wherein R C It is hydrogen or alkyl or R 2A and R 2B Together with the carbon atoms they are attached to, they form oxo groups, where R 2A and R 2B They are not both hydrogen;

[0395] R 3 It can be hydrogen, alkyl, alkenyl, ynyl or –ORA , where R A It is an alkyl group;

[0396] R 4 It is either non-existent or is hydrogen; and

[0397] Represents a single bond or a double bond, where when one When it is a double bond, then the other one... For a single bond; when two When all bonds are single bonds, then R 4 For hydrogen; and when one When it is a double bond, R 4 It does not exist;

[0398] The premise is that when R 4 It does not exist, R 2A For –OH, R 2B For hydrogen or –CF3 and R 1A and R 1B When it is –CH3, then R 3 Not hydrogen; and when R 1A and R 1B For –CH3 and R 3 When it is hydrogen, then R 2A and R 2B They do not form oxo groups together with the carbon atoms they are attached to.

[0399] In some implementation schemes, R 4 It does not exist, R 2A and R 2B One of them is –OH and R 3 It is not hydrogen.

[0400] In some embodiments, the compound of formula (II) is a compound of formula (II-A):

[0401]

[0402] In some embodiments, the compound of formula (II) is a compound of formula (II-B):

[0403]

[0404] In some embodiments, the compound of formula (II) is a compound of formula (II-C):

[0405]

[0406] In some embodiments, the compound of formula (II) is a compound of formula (II-D):

[0407]

[0408] In some embodiments, the compound of formula (II) is a compound of formula (II-E), (II-F), or (II-G):

[0409]

[0410] Where R 2C It is hydrogen or alkyl (e.g., substituted or unsubstituted alkyl) and R 3 It is an alkyl group (e.g., substituted or unsubstituted alkyl).

[0411] In some embodiments, the compound of formula (II) is a compound of formula (II-H), (II-I), or (II-J):

[0412]

[0413]

[0414] Where R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group.

[0415] In some embodiments, the compound of formula (II) is a compound of formula (II-K):

[0416]

[0417] Where R' is an alkyl group or –OR A , where R A It is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5 or 6; and m is 0, 1, 2 or 3.

[0418] In some implementation schemes, R 1A and R 1B Each is independently an unsubstituted or substituted alkyl group (e.g., haloalkyl, alkoxyalkyl, –CH3, –CH2CH3, –CH(CH3)2, –CF3 or –CH2OCH3).

[0419] In some implementation schemes, R 1A and R 1B Each is independently a substituted alkyl group (e.g., a haloalkyl group).

[0420] In some implementation schemes, R 1A It can be –CF3 or –CH2OCH3.

[0421] In some implementation schemes, R 1A and R 1BIt is an alkyl group (e.g., unsubstituted or substituted alkyl groups (e.g., –CH3)).

[0422] In some implementation schemes, R 1A and R 1B It is –CH3.

[0423] In some implementation schemes, R 1A and R 1B They form rings together with the carbon atoms they are attached to.

[0424] In some implementation schemes, R 1A For hydrogen and R 1B It can be alkyl, carbocyclic, heterocyclic, aryl, or heteroaryl.

[0425] In some implementation schemes, R 2A and R 2B Each is an alkyl group (e.g., substituted or unsubstituted alkyl groups).

[0426] In some implementation schemes, R 3 It is an alkyl group (e.g., substituted or unsubstituted alkyl).

[0427] In some implementation schemes, R 2A and R 2B Each independently consists of hydrogen and R 3 It is an alkyl group (e.g., substituted or unsubstituted alkyl).

[0428] In some implementation schemes, R 2A and R 2B Each is independently represented by –F.

[0429] In some implementation schemes, R 2A and R 2B For –CH3 and R 3 It is alkyl, alkenyl, ynyl or –OR A , where R A It is an alkyl group.

[0430] In some implementation schemes, R 2A and R 2B For –F.

[0431] In some implementation schemes, R 1A For substituted alkyl or unsubstituted C2-C6 alkyl and R 1B It is a substituted or unsubstituted C1-C6 alkyl group.

[0432] In some respects, the compound is a compound of formula (III):

[0433]

[0434] Or its pharmaceutically acceptable salt, wherein:

[0435] Each R 1A and R 1B It is an alkyl group;

[0436] R 2A and R 2B Each independently is hydrogen, –OR C or alkyl, wherein R C It is hydrogen or alkyl, or

[0437] R 2A and R 2B Together with the carbon atoms they are attached to, they form oxo groups, where R 2A and R 2B They are not both hydrogen;

[0438] R 3 It is an alkyl group;

[0439] R 4 It is either non-existent or is hydrogen; and

[0440] Represents a single bond or a double bond, where when one When it is a double bond, then the other one... For a single bond; when two When all bonds are single bonds, then R 4 For hydrogen; and when one When it is a double bond, R 4 It does not exist.

[0441] In some respects, R 1A and R 1B Each is –CH3.

[0442] In some respects, R 2A and R 2B Together with the carbon atoms they are attached to, they form oxo groups.

[0443] In some respects, R 3 It is –CH2CH3.

[0444] In some respects, R 2A For –OH and R 2B For H.

[0445] In some respects, R 2A For –CH3 and R 2B For H.

[0446] In some respects, R 2A For –OH and R 2B It is –CH3.

[0447] In some respects, R1A For –CF3.

[0448] In an alternative embodiment, the compound described herein may also contain one or more isotopic substitutions. For example, hydrogen may be... 2 H(D or deuterium) or 3 H (T or tritium); carbon can be, for example... 13 C or 14 C; oxygen can be, for example 18 O; nitrogen can be, for example 15 N, etc. In other embodiments, specific isotopes (e.g., 3 H, 13 C 14 C 18 O or 15 N) can represent 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 specific site in the compound.

[0449] Pharmaceutical Composition

[0450] In another aspect, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and an effective amount of a compound of formula (A), formula (B), formula (I), formula (II) or formula (III).

[0451] When used as a medicine, the compounds described herein are typically administered in the form of a pharmaceutical composition. This composition may be prepared in a manner known in the pharmaceutical industry and contains at least one active compound.

[0452] In one embodiment, the carrier for the pharmaceutical composition is a parenteral carrier, an oral carrier, or a topical carrier.

[0453] The present invention also relates to compounds of formula (A), formula (B), formula (I), formula (II) or formula (III) or pharmaceutical compositions thereof used as pharmaceutical products or medicines.

[0454] Typically, the compounds described herein are administered in therapeutically effective amounts. The actual amount of compound administered is usually determined by the physician based on relevant factors, including the condition being treated, the route of administration chosen, the compound actually administered, the patient's age, weight and response, and the severity of the patient's symptoms.

[0455] The pharmaceutical compositions provided herein can be administered via various routes, including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Depending on the desired route of delivery, the compounds provided herein are preferably formulated as injectable or oral compositions, or as ointments, lotions, or patches exclusively for transdermal application.

[0456] Compositions intended for oral administration may be in the form of bulk liquid solutions, suspensions, or bulk powders. However, more commonly, the composition is present in unit dosage forms to aid in precise dosing. The term "unit dosage form" refers to a physically dispersed unit suitable for a single dose in human subjects and other mammals, each unit containing a predetermined amount of active substance and suitable pharmaceutical excipients, wherein the amount of active substance is calculated to produce the desired therapeutic effect. Typical unit dosage forms include pre-filled liquid compositions, ampoules or syringes of predicted amounts, or, in the case of solid compositions, pills, tablets, or capsules. In such compositions, the compound is typically a small component (about 0.1 to 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various media or carriers, and processing aids that facilitate the formation of the desired dosage form.

[0457] Suitable liquid forms for oral administration may include appropriate aqueous or non-aqueous media, as well as buffers, suspending and dispersing agents, colorants, flavoring agents, etc. Solid forms may include, for example, any of the following ingredients or compounds with similar properties: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginate, Primogel, or corn starch; lubricants such as magnesium stearate; gliding agents such as colloidal silica; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavorings.

[0458] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As previously stated, the active compound in the composition is typically a minority component, usually about 0.05 to 10% by weight, with the remainder being the injectable carrier, etc.

[0459] Transdermal compositions are typically formulated as topical ointments or creams containing an active ingredient, typically in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, more preferably about 0.1 to about 10% by weight, and even more preferably about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredient is typically combined with paraffin or a water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with, for example, an oil-in-water emulsion base. Such transdermal formulations are known in the art and typically contain other ingredients to increase the transdermal permeation stability of the active ingredient or the formulation. All such known transdermal formulations and ingredients are included within the scope described herein.

[0460] The compounds described herein can also be administered via transdermal devices. Therefore, transdermal administration can be achieved using reservoir-type or porous membrane patches or solid matrix types.

[0461] The ingredients described above for oral, injectable, or topical application are only representative. Other materials and processing techniques are listed in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, and are incorporated herein by reference.

[0462] The ingredients listed above for oral, injectable, or topical applications are only representative. Other materials and processing techniques are listed in Part 8 of Remington's The Science and Practice of Pharmacy, 21st edition, 2005, published by Lippincott Williams & Wilkins, and are incorporated herein by reference.

[0463] The compounds of this invention can be administered in a sustained-release form or via a sustained-release drug delivery system. Descriptions of representative sustained-release materials can be found at Remington's Pharmaceutical Sciences.

[0464] 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, which consist of 6, 7, and 8 α–1,4–linked glucose units, respectively, optionally comprising one or more substitutions at the linked sugar moieties, said substituents including, but not limited to, methylation, hydroxyalkylation, acylation, and sulfonyl alkyl ether substituents. In some embodiments, the cyclodextrin is a sulfonyl alkyl ether β–cyclodextrin, for example, sulfobutyl ether β–cyclodextrin, also known as… See, for example, US 5,376,645. In some embodiments, the formulation comprises hexapropyl-β-cyclodextrin. In more specific embodiments, the formulation comprises hexapropyl-β-cyclodextrin (10-50% in water).

[0465] This invention also relates to pharmaceutically acceptable acid addition salts of compounds of formula (A), formula (B), formula (I), formula (II), or formula (III). The acids that can be used to prepare pharmaceutically acceptable salts are those that form non-toxic acid addition salts, wherein the salts are salts containing pharmaceutically acceptable anions, such as hydrochlorides, hydroiodates, hydrobromates, nitrates, sulfates, hydrogen sulfates, phosphates, acetates, lactates, citrates, tartrates, succinates, maleates, fumarates, benzoates, p-toluenesulfonates, etc.

[0466] The following formulation examples illustrate representative pharmaceutical compositions that can be prepared according to the present invention. However, the present invention is not limited to the following pharmaceutical compositions.

[0467] Exemplary Formulation 1 – Tablets: A compound of formula (A), (B), (I), (II), or (III), or a pharmaceutically acceptable salt thereof, may be mixed as a dry powder with a dry gelatin binder at a weight ratio of about 1:2. A small amount of magnesium stearate may be added as a lubricant. The mixture is then compressed in a tableting machine to form tablets of 240 to 270 mg (each tablet containing 80 to 90 mg of the active compound).

[0468] 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 as a dry powder with a starch diluent at a weight ratio of about 1:1. The mixture is then filled into 250 mg capsules (each capsule containing 125 mg of the active compound).

[0469] 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), and the resulting mixture may be blended, sieved through a 10-mesh US sieve, and then mixed with an aqueous solution of previously prepared microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg). Sodium benzoate (10 mg), flavoring agent, and coloring agent are diluted with water and added with stirring. Sufficient water may then be added to produce a total volume of 5 mL.

[0470] Exemplary Formulation 4 – Tablets: A compound of formula (A), (B), (I), (II), or (III) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a dry gelatin binder at a weight ratio of about 1:2. A small amount of magnesium stearate may be added as a lubricant. The mixture is then compressed in a tableting machine to form tablets of 450 to 900 mg (150 to 300 mg of the active compound).

[0471] Exemplary Formulation 5 – Injection: A compound of formula (A), formula (B), formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt thereof is soluble in or suspended in a buffered sterile saline injectable aqueous medium at a concentration of about 5 mg / mL.

[0472] Exemplary Formulation 6 – Tablets: A compound of formula (A), (B), (I), (II), or (III) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a dry gelatin binder at a weight ratio of about 1:2. A small amount of magnesium stearate may be added as a lubricant. The mixture is then compressed in a tableting machine to form tablets of 90 to 150 mg (each tablet containing 30 to 50 mg of the active compound).

[0473] Exemplary Formulation 7 – Tablets: A compound of formula (A), formula (B), formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, may be mixed as a dry powder with a dry gelatin binder at a weight ratio of about 1:2. A small amount of magnesium stearate may be added as a lubricant. The mixture is then compressed in a tableting machine to form tablets of 30 to 90 mg (each tablet containing 10 to 30 mg of the active compound).

[0474] Exemplary Formulation 8 – Tablets: A compound of formula (A), formula (B), formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, may be mixed as a dry powder with a dry gelatin binder at a weight ratio of about 1:2. A small amount of magnesium stearate may be added as a lubricant. The mixture is then compressed in a tableting machine to form tablets of 0.3 to 30 mg (each tablet containing 0.1 to 10 mg of the active compound).

[0475] Exemplary Formulation 9 – Tablets: A compound of formula (A), (B), (I), (II), or (III) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a dry gelatin binder at a weight ratio of about 1:2. A small amount of magnesium stearate may be added as a lubricant. The mixture is then compressed in a tableting machine to form tablets of 150 to 240 mg (each tablet containing 50 to 80 mg of the active compound).

[0476] Exemplary Formulation 10 – Tablets: A compound of formula (A), (B), (I), (II), or (III) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a dry gelatin binder at a weight ratio of about 1:2. A small amount of magnesium stearate may be added as a lubricant. The mixture is then compressed in a tableting machine to form tablets of 270 to 450 mg (each tablet containing 90 to 150 mg of the active compound).

[0477] Over a period of approximately 1 hour to 120 hours, particularly within 24 to 96 hours, the injection dose level ranges from approximately 0.1 mg / kg / hour to at least 10 mg / kg / hour. Preloading boluses of approximately 0.1 mg / kg to approximately 10 mg / kg or greater may also be administered to achieve a sufficiently stable state level. For human patients weighing 40 to 80 kg, the total maximum dose is not expected to exceed approximately 2 g / day.

[0478] For the prevention and / or treatment of long-term conditions, treatment regimens are often extended over many months or years; therefore, oral administration is preferred considering patient convenience and tolerability. For oral administration, 1 to 5 times daily, particularly 2 to 4 times daily, and typically 3 times daily are representative regimens. Using these dosing regimens, each dose provides about 0.01 to about 20 mg / kg of the compound of the invention, with preferred doses providing about 0.1 to about 10 mg / kg, and particularly about 1 to about 5 mg / kg.

[0479] Transdermal doses are typically chosen to provide similar or lower blood levels compared to injectable doses.

[0480] When used to prevent CNS disorders, the compounds described herein are administered to subjects at the dose levels described above, typically under the advice and supervision of a physician. Subjects at risk of developing a specific condition typically include those with a family history of the condition or those identified through genetic testing or screening as particularly susceptible to developing the condition.

[0481] Treatment and usage methods

[0482] The compounds of this invention, such as those of formula (A), (B), (I), (II), or (III) and their pharmaceutically acceptable salts as described herein, are generally designed to modulate NMDA function and thus act as oxidosterols for the treatment and prevention of, for example, CNS-related conditions in subjects. In some embodiments, the compounds described herein, such as those of formula (A), (B), (I), (II), or (III) and their pharmaceutically acceptable salts as described herein, are generally designed to cross the blood-brain barrier (e.g., designed to be transported across the blood-brain barrier). As used herein, modulation refers to, for example, the inhibition or enhancement of NMDA receptor function. In some embodiments, the compounds of formula (A), (B), (I), (II), or (III) or their pharmaceutically acceptable salts act as negative allosteric modulators (NAMs) of NMDA and inhibit NMDA receptor function. In some embodiments of the invention, for example, compounds of formula (A), (B), (I), (II), or (III), or pharmaceutically acceptable salts thereof, act as positive allosteric modulators (PAMs) of NMDA and enhance NMDA receptor function. In some embodiments, compounds of formula (A), (B), (I), (II), or (III), or pharmaceutically acceptable salts thereof, block or reduce the enhancement or inhibition of NMDA receptor function through naturally occurring substrates. These compounds do not act as negative allosteric modulators (NAMs) or positive allosteric modulators (PAMs) of NMDA. In some embodiments, the condition is cancer. In some embodiments, the condition is diabetes. In some embodiments, the condition is a sterol synthesis disorder. In some embodiments, the condition is a gastrointestinal (GI) condition, such as constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) (e.g., ulcerative colitis, Crohn's disease), structural conditions affecting the gastrointestinal tract, anal conditions (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas), colonic polyps, cancer, or colitis. In some embodiments, the condition is inflammatory bowel disease.

[0483] Exemplary conditions associated with NMDA regulation include, but are not limited to, gastrointestinal (GI) conditions such as constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) (e.g., ulcerative colitis, Crohn's disease), structural conditions affecting the gastrointestinal tract, anal conditions (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas), colonic polyps, cancer, colitis, and CNS conditions, such as those described herein.

[0484] Exemplary conditions associated with NMDA regulation (e.g., CNS conditions) include, but are not limited to, adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, social phobia, generalized anxiety disorder), cognitive disorders (including Alzheimer's disease and other forms of dementia, including cortical-basal dementia-progressive supranuclear palsy, frontotemporal dementia, primary progressive aphasia, Parkinson's dementia, and Lewy body dementia), dissociative disorders, eating disorders, affective disorders (including depression (e.g., postpartum depression), bipolar disorder, dysthymia, suicide), schizophrenia or other psychosis (including affective schizophrenia), sleep disorders (including insomnia), substance abuse-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations in the Shank proteome (e.g., Shank3)), and neurodevelopmental disorders (including Rett syndrome). Syndrome (including multiple sclerosis, sterol synthesis disorders, Schlein-Lennan-Oxley syndrome, pain (including acute pain, chronic pain, and neuropathic pain), seizures (including status epilepticus and monogenic forms of epilepsy such as Dravet disease, complex tuberous sclerosis (TSC), and infantile spasms), stroke, subarachnoid hemorrhage, intracerebral hemorrhage, cerebral ischemia, traumatic brain injury, movement 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 titers of anti-NMDA receptor antibodies (including anti-NMDA receptor encephalitis), neurodegenerative diseases, neuroinflammation, neuropsychiatric lupus, Niemann-Pick C disorder, and tinnitus.

[0485] In some embodiments, the compounds of the present invention, such as compounds of formula (A), (B), (I), (II) or (III), or pharmaceutically acceptable salts thereof, can be used to induce sedation or anesthesia.

[0486] In some embodiments, compounds of formula (A), (B), (I), (II), or (III), or pharmaceutically acceptable salts thereof, are used to treat or prevent adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, social phobia, generalized anxiety disorder), cognitive disorders (including Alzheimer's disease and other forms of dementia, including cortical-basal dementia-progressive supranuclear palsy, frontotemporal dementia, primary progressive aphasia, Parkinson's dementia, and Lewy body dementia), dissociative disorders, eating disorders, affective disorders (including depression (e.g., postpartum depression), bipolar disorder, dysphoric disorder, suicide), schizophrenia or other psychosis (including affective schizophrenia), sleep disorders (including insomnia), substance abuse-related disorders, personality disorders (including obsessive-compulsive personality disorder), and autism spectrum disorders (including those involving Shankton's disease). Mutations in the k-protein genome (e.g., Shank3), neurodevelopmental disorders (including Rett syndrome), multiple sclerosis, sterol synthesis disorders, Schlein-Lennan-Oxley syndrome, pain (including acute pain, chronic pain, and neuropathic pain), seizures (including status epilepticus and monogenic forms of epilepsy such as Dravet disease, complex tuberous sclerosis (TSC), and infantile spasms), stroke, subarachnoid hemorrhage, intracerebral hemorrhage, cerebral ischemia, traumatic brain injury, movement disorders (including Huntington's disease and Parkinson's disease), attention deficit, attention deficit hyperactivity disorder, metabolic encephalopathy (including phenylketonuria), postpartum psychosis, syndromes associated with high titers of anti-NMDA receptor antibodies (including anti-NMDA receptor encephalitis), neurodegenerative diseases, neuroinflammation, neuropsychiatric lupus, Niemann-Pick type C disorder, and tinnitus.

[0487] In some embodiments, compounds of formula (A), (B), (I), (II), or (III), or pharmaceutically acceptable salts thereof, are used to treat or prevent adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, social phobia, generalized anxiety disorder), cognitive disorders (including Alzheimer's disease and other forms of dementia, including cortical-basal dementia-progressive supranuclear palsy, frontotemporal dementia, primary progressive aphasia, Parkinson's dementia, and Lewy body dementia), substance abuse-related disorders, dissociative disorders, eating disorders, affective disorders (including depression (e.g., postpartum depression), bipolar disorder, dysphoric disorder, suicide), schizophrenia or other psychosis (including affective schizophrenia), personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations in the Shank proteome (e.g., Shank3)), or postpartum psychosis.

[0488] In some embodiments, compounds of formula (A), (B), (I), (II), or (III), or pharmaceutically acceptable salts thereof, are used to treat or prevent neurodevelopmental disorders (including Rett syndrome), multiple sclerosis, sterol synthesis disorders, Schlein-Lennan-Oxley syndrome, pain (including acute pain, chronic pain, and neuropathic pain), seizures (including status epilepticus and monogenic forms of epilepsy such as Dravet disease, complex tuberous sclerosis (TSC), and infantile spasms), stroke, subarachnoid hemorrhage, intracerebral hemorrhage, cerebral ischemia, traumatic brain injury, movement disorders (including Huntington's disease and Parkinson's disease), attention deficit, attention deficit hyperactivity disorder, metabolic encephalopathy (including phenylketonuria), syndromes associated with high titers of anti-NMDA receptor antibodies (including anti-NMDA receptor encephalitis), neurodegenerative diseases, neuroinflammation, neuropsychiatric lupus, Niemann-Pick type C disorder, or tinnitus.

[0489] In some embodiments, the compounds of the present invention, such as compounds of formula (A), (B), (I), (II), or (III), which act as PAM or NAMs that function as NMDA receptors, may be used to treat or prevent conditions (e.g., CNS-related conditions), including schizophrenia or other psychoses (including affective schizophrenia), sleep disorders (including insomnia), autism spectrum disorders (including those involving mutations in the Shank proteome (e.g., Shank3)), multiple sclerosis, movement disorders (including Huntington's disease and Parkinson's disease), attention deficit disorder, attention deficit hyperactivity disorder, metabolic encephalopathy (including phenylketonuria), postpartum psychosis, and syndromes associated with high titers or anti-NMDA receptor antibodies (including anti-NMDA receptor encephalitis).

[0490] In some embodiments, the compounds of the present invention, such as compounds of formula (A), (B), (I), (II), or (III), which act as NAMs that function as NMDA receptors, can be used to treat or prevent conditions (e.g., CNS-related conditions), including anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, social phobia, generalized anxiety disorder), mood disorders (including depression (e.g., postpartum depression, bipolar disorder, dysthymia, suicide), personality disorders (including obsessive-compulsive personality disorder), neurodevelopmental disorders (including Rett syndrome), pain (including acute and chronic pain), seizures (including status epilepticus and monogenic forms of epilepsy such as Dravet disease and complex tuberous sclerosis (TSC)), stroke, traumatic brain injury, adjustment disorders, neuropsychiatric lupus, and tinnitus.

[0491] In some embodiments, the compounds of the present invention, such as compounds of formula (A), (B), (I), (II), or (III), which act as PAM or NAMs that function as NMDA receptors, can be used to treat or prevent conditions (e.g., CNS-related conditions), including cognitive impairments (including Alzheimer's disease and other forms of dementia, including cortical-basal dementia-progressive supranuclear palsy, frontotemporal dementia, primary progressive aphasia, Parkinson's dementia, and Lewy body dementia), sterol synthesis disorders, and eating disorders.

[0492] In another aspect, methods are provided for treating or preventing brain excitability in subjects who are susceptible to or suffer from conditions related to brain excitability, including administering to the subject an effective amount of a compound of the present invention, such as a compound of formula (A), formula (B), formula (I), formula (II) or formula (III), or a pharmaceutically acceptable salt thereof.

[0493] In another aspect, the present invention provides combinations of the compounds of the invention, such as compounds of formula (A), (B), (I), (II), or (III), or pharmaceutically acceptable salts thereof, and another pharmacologically active agent. The compounds provided herein can be administered as individual active agents, or they can be administered in combination with other agents. Combination administration can be performed by any technique readily apparent to those skilled in the art, including, for example, separate, sequential, simultaneous, and alternating administration.

[0494] Movement disorders

[0495] This article also describes methods for treating movement disorders. As used herein, “movement disorder” refers to a variety of diseases and disorders associated with hyperactivity and related abnormalities in muscle control. Exemplary movement disorders include, but are not limited to, Parkinson’s disease and Parkinson’s syndrome (particularly defined by bradykinesia), dystonia, chorea and Huntington’s disease, ataxia, tremor (e.g., essential tremor), myoclonus and panic attacks, tics and Tourette syndrome, restless legs syndrome, stiff-person syndrome, and gait disorders.

[0496] Tremor is an involuntary, irregular, rhythmic contraction and relaxation of muscles that may involve vibration or twitching of one or more body parts (e.g., hands, arms, eyes, face, head, vocal cords, trunk, legs). Tremors can be categorized into hereditary, degenerative, and primary diseases such as Wilson's disease, Parkinson's disease, and essential tremor; metabolic diseases (e.g., thyroid-parathyroid disorders, liver diseases, and hypoglycemia); peripheral neuropathy (associated with Charcot-Marie-Tooth disease, Roussy-Levy syndrome, diabetes, and complex regional pain syndrome); toxins (nicotine, mercury, lead, CO, manganese, arsenic, toluene); drug-induced disorders (narcotic anesthetics, tricyclic antidepressants, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremor can be classified into physiological tremor, exacerbated physiological tremor, essential tremor syndrome (including typical essential tremor, essential orthostatic tremor, task- and position-specific tremor), dystonia tremor, Parkinson's disease tremor, cerebellar tremor, Holmes' tremor (i.e., red nucleus tremor), palatal tremor, neurogenic tremor, toxic or drug-induced tremor, and psychogenic tremor. Other forms of tremor include cerebellar tremor or intention tremor, dystonia tremor, essential tremor, orthostatic tremor, Parkinson's disease tremor, physiological tremor, psychogenic tremor, or red nucleus tremor.

[0497] Cerebellar tremor, or intention tremor, is a slow, widespread tremor of the limbs that occurs after purposeful movement. Cerebellar tremor is caused by cerebellar damage or injury resulting from conditions such as tumors, stroke, or diseases (e.g., multiple sclerosis, hereditary degenerative diseases).

[0498] Dystonic tremor occurs in individuals affected by dystonia, a movement disorder characterized by persistent, involuntary muscle contractions that cause twisting and repetitive movements and / or pain and abnormal postures or positions. Dystonic tremor can affect any muscle in the body. It occurs irregularly and is usually relieved by complete rest.

[0499] Essential tremor, or benign essential tremor, is the most common type of tremor. Essential tremor may be mild and non-progressive in some cases, and may develop slowly, starting on one side of the body but affecting both sides within 3 years. The hands are most commonly affected, but the head, voice, tongue, legs, and trunk may also be involved. The frequency of tremors may decrease with age, but the severity may increase. Elevated mood, stress, fever, fatigue, or hypoglycemia may trigger tremors and / or increase their severity. Symptoms typically develop over time and can be visible and persistent after onset.

[0500] Orthostatic tremor is characterized by rapid (e.g., greater than 12 Hz) rhythmic muscle contractions that occur immediately after standing up in the legs and trunk. Spasms are felt in the thighs and legs, and the patient may sway uncontrollably when asked to stand in one position. Orthostatic tremor can occur in patients with essential tremor.

[0501] Parkinson's tremor is caused by damage to brain structures that control movement. It is often a precursor to Parkinson's disease and is commonly perceived as a "pill-rolling" motion in the hands, but can also affect the jaw, lips, legs, and trunk. Onset of Parkinson's tremor typically begins after age 60. The movement begins in one limb or side of the body and can progress to include the other side.

[0502] Physiological tremor can occur in normal individuals and is not clinically significant. It can be seen in all voluntary muscle groups. Physiological tremor can be caused by certain medications, alcohol withdrawal, or medical conditions including overactive thyroid and hypoglycemia. The tremor typically has a frequency of approximately 10 Hz.

[0503] Psychogenic tremor, or hysterical tremor, can occur at rest or during postural or dynamic movement. Patients with psychogenic tremor may have conversion disorder or other mental illnesses.

[0504] The characteristic feature of red nucleus tremor is a coarse, slow tremor that can be present at rest, in posture, and with intention. The tremor is associated with conditions affecting the red nucleus in the midbrain, namely classic atypical stroke.

[0505] Parkinson's disease affects nerve cells in the brain that produce dopamine. Symptoms include muscle rigidity, tremor, and changes in speech and gait. Parkinson's disease is characterized by tremor, bradykinesia, rigidity, and postural instability. While Parkinson's disease presents with symptoms of Parkinson's disease, the symptoms are more complex than those of a progressive neurodegenerative disease.

[0506] Dystonia is a movement disorder characterized by persistent or intermittent muscle contractions that result in abnormal and often repetitive movements or postures. Dystonia movements can be patterned, distorted, and may involve tremors. Dystonia is typically triggered or exacerbated by voluntary movements and is accompanied by spillover muscle activation.

[0507] Chorea is a neurological disorder characterized by spasmodic, involuntary movements that typically affect the shoulders, hips, and face.

[0508] Huntington's disease is a genetic disorder that causes nerve cells in the brain to be wasted. Symptoms include uncontrolled movement, clumsiness, and balance problems. Huntington's disease can impair walking, speaking, and swallowing.

[0509] Ataxia is the loss of complete control over bodily movements and may affect the fingers, hands, arms, legs, body, speech, and eye movements.

[0510] Myoclonus and panic are responses to sudden and unexpected stimuli, which can be acoustic, tactile, visual, or vestibular.

[0511] A tic is an involuntary movement that typically occurs suddenly, briefly, and repeatedly, but is non-rhythmic, usually mimicking normal behavior and often occurring in the context of normal activity. Tics can be classified as motor or vocal; those associated with movement are motor tics, and those associated with sound are vocal tics. Tics can be characterized as simple or complex. For example, a simple motor tic involves only a few muscles limited to a specific body part.

[0512] Tourette syndrome is a hereditary neuropsychiatric disorder that manifests in childhood and is characterized by multiple motor tics and at least one vocal tic.

[0513] Restless legs syndrome is a neurosensory-motor disorder characterized by an overwhelming urge to move the legs at rest.

[0514] Stiff-person syndrome is a progressive movement disorder characterized by involuntary, painful spasms and muscle rigidity, typically involving the lower back and legs. It usually results in a stiff gait with exaggerated lumbar lordosis. Characteristic abnormalities in EMG recordings of continuous motor unit activity involving paravertebral muscles are commonly observed. Variants include "stiff limb syndrome," which produces focal stiffness typically affecting the distal leg and foot.

[0515] Gait disorders refer to abnormalities in the way or type of walking caused by neuromuscular, arthritis, or other bodily changes. Gait is classified according to the system responsible for abnormal movement, including hemiplegic gait, diplegic gait, neuropathic gait, myopathic gait, Parkinson's disease gait, chorea-like gait, ataxia-like gait, and sensory gait.

[0516] Emotional Disorders

[0517] This article also provides methods for treating mood disorders such as clinical depression, postpartum depression or postpartum melancholia, atypical depression, melancholic depression, psychotic major depression, catatonic depression, seasonal affective disorder, dysphoric mood, bipolar disorder, depressive personality disorder, recurrent transient depression, mild depression, bipolar disorder or manic depression, depression caused by chronic medical conditions, treatment-resistant depression, treatment-resistant depression, suicide, suicidal ideation or suicidal behavior.

[0518] Clinical depression, also known as major depressive disorder (MDD), severe depression, unipolar depression, unipolar illness, and recurrent depression, is a mental disorder characterized by a generalized and persistent low mood, accompanied by low self-esteem and loss of interest or pleasure in normally enjoyable activities. Some people with clinical depression experience difficulty sleeping or losing weight and often feel anxious and irritable. Clinical depression affects an individual's feelings, thoughts, and behaviors and can lead to a variety of emotional and physical problems. People with clinical depression may experience difficulty in daily activities and feel that life is not worth living.

[0519] Postpartum depression (PND), also known as postpartum melancholia (PPD), is a clinical depression that affects women after childbirth. Symptoms may include sadness, fatigue, changes in sleep and eating habits, decreased libido, crying episodes, anxiety, and irritability. In some implementations, the PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein). In some implementations, the PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein).

[0520] In some implementations, subjects with PND also experience symptoms of depression or postpartum depression during pregnancy. This type of depression is referred to herein as perinatal depression. In one implementation, subjects experiencing perinatal depression have an increased risk of developing PND.

[0521] Atypical depression (AD) is characterized by mood responsiveness (e.g., anomalous lack of interest) and positivity, significant weight gain, or increased appetite. Patients with AD may also experience excessive sleepiness or somnolence (hypersomnia), heaviness in the limbs, and significant social impairment due to hypersensitivity to perceived interpersonal rejection.

[0522] Melancholic depression is characterized by loss of pleasure in most or all activities (loss of interest), inability to respond to pleasant stimuli, more pronounced depressive mood than sadness or loss, excessive weight loss, or excessive guilt.

[0523] Major psychotic depression (PMD) or psychotic depression refers to a severe depressive episode, particularly a melancholic one, in which the individual experiences psychotic symptoms such as delusions and hallucinations.

[0524] Catatonic depression is a severe form of depression involving disordered motor behavior and other symptoms. Individuals may become mute and comatose, and either remain immobile or exhibit aimless or strange movements.

[0525] Seasonal affective disorder (SAD) is a type of seasonal depression in which individuals have a seasonal pattern of depressive episodes that occur in the fall or winter.

[0526] Dysphoria refers to a condition associated with unipolar depression in which the same physical and cognitive problems are present. These are less severe and tend to last longer (e.g., at least 2 years).

[0527] Double depression refers to a severe depressed mood (dysthymia) that lasts for at least 2 years and occasionally includes major depressive disorder.

[0528] Depressive personality disorder (DPD) refers to a personality disorder characterized by depressive features.

[0529] Recurrent transient depression (RBD) is a condition in which an individual experiences depressive episodes approximately once a month, each lasting two weeks or less, usually less than two to three days.

[0530] Mild depressive disorder or mild depression is defined as depression in which at least two of the symptoms persist for two weeks.

[0531] Bipolar disorder, or manic-depressive illness, causes extreme mood swings, including highs (mania or hypomania) and lows (depression). During a manic episode, an individual may feel or behave abnormally happy, energetic, or irritable. They often make ill-considered decisions without regard for consequences. They typically have a reduced need for sleep. During a depressive episode, they may experience crying spells, poor eye contact, and negative views of life. People with this disorder have a greater than 6% risk of resuicide over 20 years, while the incidence of self-harm is 30-40%. Other mental health problems, such as anxiety disorders and substance use disorders, are often associated with bipolar disorder.

[0532] Depression caused by chronic medical conditions refers to depression caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, or chronic stress.

[0533] Treatment-resistant depression refers to a condition in which an individual has received treatment for depression but whose symptoms have not improved. For example, antidepressants or psychotherapy (psychotherapy) do not alleviate depressive symptoms in patients with treatment-resistant depression. In some cases, individuals with treatment-resistant depression may experience symptom improvement but relapse. Treatment-resistant depression occurs in patients who are resistant to standard medications, including tricyclic antidepressants, MAOIs, SSRIs, dual and triple uptake inhibitors, and / or anxiolytics, as well as nonpharmacological treatments (such as psychotherapy, electroconvulsive therapy, vagus nerve stimulation, and / or transcranial magnetic stimulation).

[0534] Suicide, suicidal ideation, and suicidal behavior refer to an individual's tendency to commit suicide. Suicidal ideation involves thoughts or abnormal focus on suicide. The range of suicidal ideation varies greatly, from fleeting thoughts to broad ideas, detailed plans, role-playing, and incomplete attempts. Symptoms include talking about suicide, acquiring means of suicide, withdrawing from social contact, focusing on death, feeling confused or hopeless about the situation, increased alcohol or drug use, doing risky or self-destructive things, and saying goodbye to people in a farewell manner.

[0535] Symptoms of depression include persistent anxiety or sadness, helplessness, hopelessness, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, physical challenge, loss of interest in enjoyable activities or hobbies, difficulty concentrating, decreased 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 may vary from person to person. Symptoms of depression and their remission can be determined by a physician or psychologist (e.g., through a mental status examination).

[0536] Anxiety disorder

[0537] This article provides methods for treating anxiety disorders. Anxiety disorder is a broad term that encompasses several different forms of abnormal and pathological fear and anxiety. Current diagnostic criteria for mental illness identify a wide variety of anxiety disorders.

[0538] Generalized anxiety disorder (GAD) is a common chronic condition characterized by persistent anxiety without focus on any particular object or situation. People with GAD experience nonspecific, persistent fear and worry and become overly preoccupied with daily affairs. GAD is the most common anxiety disorder affecting older adults.

[0539] In panic disorder, a person experiences brief attacks of intense terror and anxiety, typically characterized by tremors, shaking, confusion, dizziness, nausea, and difficulty breathing. These panic attacks, defined by the APA as sudden onset of fear or discomfort that peaks within ten minutes and can last for hours, can be triggered by stress, fear, or even physical activity; however, the exact cause is not well understood. In addition to recurrent, unexpected panic attacks, a diagnosis of panic disorder requires that the attacks have chronic consequences: either worry about the potential effects of the attack, persistent worry about future attacks, or significant changes in attack-related behavior. Therefore, people with panic disorder may experience symptoms even outside of specific panic attacks. Often, people with panic disorder notice normal changes in their heart rate, leading them to believe there is something wrong with their heart or that they are about to have another panic attack. In some cases, heightened cognitive functioning (hypervigilance) occurs during a panic attack, where any perceived physiological changes are interpreted as potentially life-threatening illness (i.e., extreme hypochondria).

[0540] Obsessive-compulsive disorder (OCD) is a type of anxiety disorder characterized by repetitive obsessive thoughts (distressing, persistent, and intrusive ideas or images) and compulsive behaviors (that lead to the performance of specific actions or rituals). The thought patterns of OCD can be likened to superstition because they involve beliefs in causality that does not actually exist. This process is often completely illogical; for example, the compulsive adoption of walking in a certain pattern may be used to alleviate fixated thoughts of impending harm. In many cases, the compulsions are completely inexplicable, simply an impulse to complete a ritual triggered by tension. In rare cases, individuals with OCD may only have fixated thoughts without overt compulsive behaviors; even fewer victims may only experience compulsive behaviors.

[0541] The single largest category of anxiety disorders is phobias, which includes all situations in which fear and anxiety are triggered by specific stimuli or circumstances. Patients typically anticipate terrible consequences of encountering the object they fear, which can be anything from animals and places to bodily fluids.

[0542] Post-traumatic stress disorder, or PTSD, is an anxiety disorder caused by a traumatic experience. PTSD can be caused by extreme situations such as combat, rape, hostage situations, or even serious accidents. It can also be due to prolonged (chronic) exposure to severe stressors, such as a soldier enduring individual combat but unable to cope with sustained combat. Common symptoms include flashbacks, avoidance behavior, and depression.

[0543] epilepsy

[0544] Epilepsy is a brain disorder characterized by recurrent seizures over time. Types of epilepsy can include, but are not limited to, generalized epilepsy, such as childhood absence epilepsy, juvenile myoclonic epilepsy, epilepsy with grand mal seizures during wakefulness, West syndrome, Lennox-Gastaut syndrome, and partial epilepsy, such as temporal lobe epilepsy, frontal lobe epilepsy, and benign focal epilepsy in children.

[0545] Epilepsy formation

[0546] Epilepsy development is a gradual process by which a normal brain develops into a condition known as epilepsy (a chronic condition in which seizures occur). Epilepsy is caused by neuronal damage resulting from an initial injury (e.g., status epilepticus).

[0547] Status epilepticus (SE)

[0548] Status epilepticus (SE) can include, for example, convulsive status epilepticus, such as early status epilepticus, definitive status epilepticus, refractory status epilepticus, and ultra-refractory status epilepticus; nonconvulsive status epilepticus, such as generalized status epilepticus and complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epileptic seizures and can include early status epilepticus, definitive status epilepticus, refractory status epilepticus, and ultra-refractory status epilepticus. Early status epilepticus is treated with first-line therapy. Definitive status epilepticus is characterized by status epileptic seizures that persist despite treatment with first-line therapy and the administration of second-line therapy. Refractory status epilepticus is characterized by status epileptic seizures that persist despite treatment with first-line and second-line therapy and is usually treated with general anesthetics. Ultra-refractory status epilepticus is characterized by status epileptic seizures that persist despite treatment with first-line, second-line, and general anesthesia for 24 hours or longer.

[0549] Nonconvulsive status epilepticus can include, for example, focal nonconvulsive status epilepticus, such as complex partial nonconvulsive status epilepticus, simple partial nonconvulsive status epilepticus, and minimal nonconvulsive status epilepticus; and generalized nonconvulsive status epilepticus, such as delayed absence nonconvulsive status epilepticus, atypical absence nonconvulsive status epilepticus, or typical absence nonconvulsive status epilepticus.

[0550] Seizures

[0551] An epileptic seizure is a physical or behavioral change that occurs following an abnormal electrical activity in the brain. The term "epileptic seizure" is often used interchangeably with "convulsion." A spasm refers to a rapid and uncontrollable shaking of the body. During a convulsion, the body's muscles repeatedly contract and relax.

[0552] Based on behavioral patterns and brain activity, epileptic seizures are classified into two main categories: generalized and partial (also known as focal or lesion-related). Classifying seizure types helps doctors diagnose whether a patient has epilepsy.

[0553] Generalized seizures are produced by electrical impulses from the entire brain, while partial seizures are produced (at least initially) by electrical impulses in a relatively small part of the brain. The part of the brain that produces a seizure is sometimes referred to as a lesion.

[0554] There are six types of generalized tonic-clonic seizures. The most common, most noticeable, and most well-known is the generalized tonic-clonic seizure, also known as a grand mal seizure. In this type of seizure, the patient loses consciousness and usually falls to the ground. Following the loss of consciousness is a generalized tonic-clonic phase (called the "tonic" phase of the seizure) lasting 30 to 60 seconds, followed by a violent convulsion (the "clonic" phase) lasting 30 to 60 seconds, after which the patient enters a deep sleep (the "postictal" or post-ictal phase). Injuries and accidents such as tongue biting and urinary incontinence can occur during a grand mal seizure.

[0555] Absence seizures cause brief loss of consciousness (lasting only a few seconds), with few or no symptoms. Patients (usually children) typically stop what they are doing and stare blankly. These seizures begin and end abruptly and can occur several times a day. Patients are usually unaware that they are having a seizure unless they become aware of “losing time.”

[0556] Myoclonic seizures consist of sporadic convulsions, usually on both sides of the body. Patients sometimes describe the convulsions as brief electric shocks. In the event of violence, these seizures may cause falls or involuntary throwing of objects.

[0557] Clonic seizures are repetitive, rhythmic jerks that involve both sides of the body simultaneously.

[0558] A characteristic feature of tonic-clonic seizures is muscle stiffness.

[0559] Atonic seizures involve a sudden and generalized loss of muscle tone, particularly in the arms and legs, which often leads to falls.

[0560] The epileptic seizures described in this article may include: epileptic seizures; acute repetitive seizures; clustered seizures; continuous seizures; uninterrupted seizures; prolonged seizures; recurrent seizures; status epileptic seizures, such as refractory convulsive status epilepticus, nonconvulsive status epileptic seizures; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondary generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign Rolandic seizures; febrile seizures; emotional seizures; focal seizures; gelastic seizures; generalized tonic-clonic seizures; infantile spasms; Jacksonian seizures. Seizures; numerous bilateral myoclonic seizures; multifocal seizures; neonatal paroxysmal seizures; nocturnal seizures; occipital lobe seizures; post-traumatic seizures; minimal seizures; Sylvan seizures; visual reflex seizures; or seizures following drug withdrawal. In some implementations, the seizures are generalized seizures associated with Dravet syndrome, Rengoir syndrome, complex tuberous sclerosis, Rett syndrome, or PCDH19 in female pediatric epilepsy.

[0561] Example 1: Synthesis of 61

[0562]

[0563] Overview:

[0564]

[0565] Synthesis 1

[0566]

[0567] t-BuOK (404 g, 3.6 mol) was added to a mixture of MePPh3Br (1.28 kg, 3.6 mol) in THF (4.5 L) at 15 °C and N2. The resulting mixture was stirred at 50 °C for 30 min. Pregnenolone (950 g, 2.9 mol) was added in portions at below 65 °C. The reaction mixture was stirred at 50 °C for 1 h. The combined mixture was quenched at 15 °C with a saturated aqueous solution of NH4Cl (1 L). The THF layer was separated. The aqueous solution was extracted with EtOAc (2 x 2 L). The combined organic phases were concentrated under vacuum to give a solid. The solid was further purified by grinding with MeOH / H2O (1:1, 15 L) and refluxed to give 1 (940 g, 99%), which was a solid.

[0568] 1 H NMR (400MHz, CDCl3) δ5.40-5.32 (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).

[0569] Synthesis 2

[0570]

[0571] At 35°C, DMP (2.14 kg, 5.08 mol) was added in portions to a solution of 1 (800 g, 2.54 mol) in DCM (8 L). The reaction mixture was stirred at 35°C for 20 minutes. The reaction mixture was filtered. The filter cake was washed with DCM (3 x 1 L). The combined organic phases were washed with a saturated Na₂S₂O₃ / saturated NaHCO₃ aqueous solution (3:1, 2 x 1.5 L) and brine (1.5 L), dried over Na₂SO₄, filtered, and concentrated under vacuum to give 2 (794 g, crude), which was a solid and used directly in the next step.

[0572] Synthesis 3

[0573]

[0574] Under a nitrogen atmosphere below 25°C, AlMe3 (2.14 L, 2.0 M toluene solution, 4.28 mol) was added dropwise to a solution of BHT (1.97 kg, 8.94 mol) in toluene (1 L). The resulting mixture was stirred at 25°C for 1 hour. 2 (794 g, 85 wt%, 2.16 mol) of Mg2+ 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 diethyl ether solution, 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 citric acid (3 L) and extracted with EtOAc (2 x 2 L). The combined organic phase was washed with brine (2 L), dried with Na2SO4, filtered and concentrated under vacuum to obtain a residue, which was then ground with MeCN (3 L) at 25 °C to obtain 3 (340 g, 43%), which was a solid.

[0575] 1 H NMR (400MHz, CDCl3) δ5.34-5.26 (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, 8H), 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).

[0576] Synthesis 4

[0577]

[0578] At 0 °C and N2, 3 (100 g, 304 mmol) was dissolved in 9-BBN (1.21 L, 0.5 M in THF, 608 mmol). The solution was stirred at 65 °C for 1 hour and then cooled again to 10 °C. A large amount of solid precipitated. Ethanol (279 g, 6080 mmol) and an aqueous solution of NaOH (304 mL, 5 M, 1520 mmol) were added dropwise to the mixture below 10 °C to give a clear solution. Then, hydrogen peroxide (343 g, 30% in water, 3040 mmol) was added dropwise below 10 °C. The reaction mixture was stirred at 75 °C for 1 hour. After cooling again to 20 °C, a solid precipitated and was collected by filtration. The filter cake was washed with water (3 x 500 mL), dried under vacuum, and the solid was ground in ethanol (1.5 L) under reflux to give 4 (92 g, 87.6%), which was a solid.

[0579] 1 H NMR (400MHz, CDCl3) δ5.31-5.29 (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).

[0580] Synthesize 5

[0581]

[0582] At 15°C, TsCl (204 g, 1071 mmol) was added to a solution of 4 (124.5 g, 357 mmol) in chloroform (1 L) and pyridine (700 mL). The mixture was stirred at 15°C for 2 hours. The mixture was then concentrated under vacuum to remove most of the chloroform. The pyridine mixture was added to water (6 L). A solid was obtained and collected by filtration, and washed with water (6 x 1 L). The solid was dissolved in DCM (3.5 L), dried with Na2SO4, filtered, and concentrated under vacuum to give 5 (163 g, 92%), which was a solid.

[0583] 1 H NMR (400MHz, CDCl3) δ7.78 (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).

[0584] Synthesis 61

[0585]

[0586] At 15°C, KI (258 g, 1560 mmol) was added to a solution of 5 (163 g, 325 mmol) in DMF (1.7 L). 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 obtained from 83 g of 5. The combined mixture was poured into water (20 L) and some solid was obtained. The mixture was filtered and the filter cake was washed with water (3 x 2 L). The resulting filter cake was dissolved in DCM (5 L), washed with water (2 x 1 L) and brine (2 x 1 L), dried with Na2SO4, filtered, and concentrated under vacuum to give a crude product, which was a solid. This product was recrystallized in toluene (2.5 L) to give 61 (150 g, 65%), which was a solid. The recrystallization filtrate was concentrated under vacuum to obtain crude 61 (30g), which is a solid.

[0587] 1 H NMR (400MHz, CDCl3) δ7.91 (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).

[0588] LCMS Rt = 2.057 min in 3.0 min chromatogram, 30-90 AB, purity 100%, MS ESI C 29 H 41 O2S[M+H-H2O] + The calculated value is 453, and the measured value is 453.

[0589] Example 2: Synthesis of Epoxides

[0590]

[0591] Me3SI (4.18 g, 20.5 mmol) was added to a suspension of t-BuOK (3.53 g, 31.6 mmol) in THF (30 mL) at 15 °C under N2. The suspension was stirred at 15 °C for 30 min. At 15 °C, a solution of 21 (2 g, 15.8 mmol) in 10 mL THF was added dropwise to the mixture. The mixture was stirred at 15 °C for 16 h. The mixture was quenched with saturated NH4Cl (100 mL) and extracted with EtOAc (3 x 150 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under vacuum to give 22 (1.8 g, 81%), which was a liquid.

[0592] 1 H NMR (400MHz, CDCl3) δ2.58 (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).

[0593] Example 3: Synthesis of 71

[0594]

[0595] Overview:

[0596]

[0597] Compound 4-2 was synthesized. At room temperature, HATU (46.3 g, 121.8 mmol) and DIPEA (45.9 g, 355.2 mmol) were added to a solution of 4-1 (38 g, 101.5 mmol) in THF (400 mL). The mixture was stirred for 1 h, and N,O-dimethylhydroxylamine hydrochloride (19.8 g, 203 mmol) was added. The mixture was stirred again at room temperature for 6 h. The reaction mixture was concentrated, poured into water, extracted with EtOAc, washed with water, dried over Na2SO4, and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (elution: PE:EA = 3:1) to give the desired product 4-2 (24 g, 57%) as a solid.

[0598] 1H 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).

[0599] Compound 4-3 was synthesized. At 0 °C, Dess-Martin reagent (28 g, 67.04 mmol, 2.0 eq) was added fractionally to a solution of compound 4-2 (14 g, 33.52 mmol, 1.0 eq) in anhydrous CH2Cl2 (600 mL). The reaction mixture was then stirred at room temperature for 6.5 h. TLC (PE:EA = 3:1) showed complete depletion of the starting material. The mixture was quenched with a saturated aqueous solution of NaHCO3 / Na2S2O3 (1:3) (800 mL). The organic phase was washed with brine (500 mL), dried over Na2SO4, and the solvent was evaporated to give crude product 4-3 (14.0 g, 100%).

[0600] Compound 4-4 was synthesized. At -78 °C under nitrogen, a solution of 4-3 (14.0 g, 33.7 mmol, 1.0 eq) in toluene (10 mL) was added dropwise. The toluene solution of MAD was freshly prepared by adding a Me3Al solution (50.5 mL, 101.00 mmol, 2 M hexane solution) to a stirred solution of 2,6-di-tert-butyl-4-methylphenol (44.4 g, 202 mmol) in toluene (200 mL) and stirring at room temperature for 1 h. The reaction mixture was then stirred for 30 min, and a MeMgBr solution (33.7 mL, 101 mmol, 3.0 eq, 3 M in diethyl ether) was added dropwise at -78 °C. The reaction mixture was then warmed to 25 °C and stirred at that temperature for 12 h. TLC (PE:EA = 3:1) showed complete depletion of the starting material. The mixture was poured into a saturated NH4Cl aqueous solution (200 mL) and extracted with EtOAc (200 mL x 2). The combined organic phases were dried over Na2SO4 and the solvent was evaporated to obtain a crude product. The crude product was purified by silica gel column chromatography (elution: PE:EA = 3:1) to obtain a pure target substance (7.5 g, 52%) as a powder.

[0601] 1 H NMR: (400MHz, CDCl3) δ5.30 (d, J=5.2Hz, 1H), 3.69 (s, 3H), 3.17 (s, 3H), 2.50-2.3 0 (m, 3H), 2.05-1.70 (m, 7H), 1.52-1.30 (m, 9H), 1.20-0.90 (m, 15H), 0.68 (s, 3H).

[0602] Compound 3-1 was synthesized. Under nitrogen atmosphere at room temperature, MeMgBr solution (29 mL, 87 mmol, 5.0 eq, 3 M THF) was added dropwise over 30 minutes to a solution of compound 4-4 (7.5 g, 17.4 mmol, 1.0 eq) in 150 mL of THF. The reaction mixture was then stirred at room temperature for 12 h. TLC (PE:EA = 1:1) showed complete depletion of the starting material. The mixture was poured into a saturated aqueous solution of NH4Cl (200 mL) and extracted with EtOAc (150 mL x 2). The combined organic phases were dried over Na2SO4 and the solvent was evaporated to give a crude product. The crude product was purified by silica gel column chromatography (elution: PE:EA = 4:1) to give product 3-1 (5.2 g, 77%) as a powder.

[0603] 1 H NMR: (400MHz, CDCl3) δ5.30 (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).

[0604] Synthesizing 3-2. TMSCF3 (1.53 mL, 10.35 mmol) was added to a suspension of 3-1 (400 mg, 1.035 mmol) and CsF (76 mg) in toluene / THF (20 mL, 8 / 1), and the mixture was stirred at room temperature under nitrogen for 20 min. TLC (petroleum ether: ethyl acetate = 3 / 1) showed complete depletion of the starting material. TBAF solution (6.8 mL, 1 M in THF) was added, and the mixture was stirred at room temperature for 4 h. 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 (eluent: petroleum ether: ethyl acetate = 20:1) to give 3-2 (220 mg, 46%) as a solid.

[0605] 1 H NMR: (400MHz, CDCl3) δ5.31 (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.)

[0606] Synthesis of 71. Compound 3-2 (1.2 g, 2.63 mmol) was isolated by SFC to give product 71 (400 mg).

[0607] 1 H NMR (71): (400MHz, CDCl3) δ5.32 (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).

[0608] Example 4: Synthesis of 1201

[0609]

[0610] At 30°C, DMP (108 g, 256 mmol) was added to a solution of 001-4 (50 g, 128 mmol) in DCM (800 mL). The reaction mixture was stirred at 30°C for 10 minutes. H2O (2.3 g, 128 mmol) was added dropwise. The reaction mixture was quenched with a saturated NaHCO3 aqueous solution (500 mL) until the pH of the aqueous layer became approximately 9. The mixture was filtered. The DCM layer was separated and the aqueous layer was extracted with DCM (100 mL). The combined organic phases were washed with a saturated Na2S2O3 aqueous solution (600 mL) and brine (500 mL), dried over Na2SO4, filtered, and concentrated to give 55 (108 g, crude), which was an oil. The reaction was performed in duplicate.

[0611] 1H NMR (400MHz, CDCl3) δ5.30-5.26 (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), 1.44-1.19(m, 3H), 1.17(s, 3H), 1.15-0.97(m, 5H), 0.96-0.88(m, 3H), 0.70(s, 3H).

[0612]

[0613] Under nitrogen atmosphere at 0°C, trimethylaluminum (2M in toluene, 418 mL, 837 mmol) was added dropwise to a solution of BHT (367 g, 1.67 mmol) in toluene (1000 mL). The mixture was stirred at 0°C for 30 min and used directly as a solution of MAD (0.59 M in toluene) without further purification. Under nitrogen atmosphere at -78°C, a solution of 55 (108 g, 279 mmol) in toluene (500 mL) was added dropwise to a solution of MAD (0.59 M in toluene, 1410 mL, 837 mmol). The mixture was stirred at -78°C for 30 min. EtMgBr (3M in diethyl ether, 278 mL, 837 mmol, 3M in diethyl ether) was added dropwise. The resulting mixture was stirred at -78°C for 1 h. The reaction mixture was poured into an ice-cooled aqueous solution of citric acid (1000 mL) and extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (0–20% EtOAc in PE) to give 1201 (95 g, impure), which was an oil. The reaction was performed in duplicate.

[0614] 1 H (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, 5 H), 1.47-1.22(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).

[0615] Example 5: Synthesis of U6477 and U6478

[0616]

[0617] Overview:

[0618]

[0619] The experiment for intermediate 61 can be seen in Example 1 of this paper. The synthesis of this epoxide can be seen in Example 2 of this paper.

[0620] Synthetic 62

[0621]

[0622] Add n-BuLi (6.60 mL, 2.5 M in hexane, 16.5 mmol) to THF (5 mL). Then, at -70 °C, add a solution of 61 (3.00 g, 6.37 mmol) in THF (30 mL). Stir the mixture at -70 °C for 1 h. Add 6,6-dimethyl-1-oxaspiro[2.5]octane (1.78 g, 12.7 mmol) at -70 °C. After stirring at -70 °C for another 1 h, warm the mixture to 25 °C and stir for 16 h, then treat with NH4Cl (50 mL, saturated aqueous solution). Extract the mixture with EtOAc (2 x 30 mL). Separate the organic layer, dry with Na2SO4, filter and concentrate to give 62 (4.00 g, crude), which is a solid.

[0623] Synthesis 63

[0624]

[0625] NiCl2 (61.5 mg, 0.654 mmol) was added to a solution of 62 (4.00 g, 6.54 mmol) in MeOH (200 mL) and heated to 60 °C. Magnesium powder (6.34 g, 261 mmol) was added in portions at 60 °C. The mixture was stirred at 60 °C for 1 h. The mixture was quenched with HCl (200 mL, 2 M) until the reaction became clear and extracted with EtOAc (3 x 200 mL). The combined organic phases were dried over Na2SO4, filtered, concentrated, and purified by rapid column chromatography (0-15% EtOAc in PE) to give 63 (1.20 g, 39%) as a solid.

[0626] 1H NMR 63 (400MHz, CDCl3) δ5.32-5.28 (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).

[0627] Synthetic 64

[0628]

[0629] Molecular sieve (200 mg) and tert-butyl hydroperoxide (4.23 mL, 25.4 mmol, 6 M in decane) were added to a solution of 63 (2.00 g, 4.24 mmol) in ethyl acetate (120 mL). The suspension was stirred at 25 °C under a nitrogen atmosphere for 30 min, and then manganese(III) acetate dihydrate (340 mg, 1.27 mmol) was added in one batch. The reaction mixture was stirred at 25 °C for 48 h. The solid was filtered off, and the filtrate was washed with Na₂SO₃ (200 mL), brine (200 mL), and dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0–15% EtOAc in DCM) to give 64 (1.10 g, 54%) as a solid.

[0630] 1 H NMR 64 (400MHz, CDCl3) δ5.66 (s, 1H), 2.61-2.55 (m, 1H), 2.45-2.34 (m, 1H), 2.28-2.19 (m, 2H), 2.08-1.78(m, 5H), 1.68-1.50(m, 9H), 1.50-1.08(m, 21H), 0.98-0.83(m, 9H), 0.68(s, 3H).

[0631] Synthesize 65

[0632]

[0633] A solution of 64 (500 mg, 1.03 mmol) was added dropwise to a solution of TMSCH2Li (0.56 M in hexane, 9.19 mL, 5.15 mmol) in anhydrous THF (25 mL) under nitrogen atmosphere at -40 °C. The mixture was stirred at -40 °C for 4 hours and gradually heated to 20 °C, then stirred again at 20 °C for 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 EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (0–20% EtOAc in PE) to give 65 (220 mg, 44%) as a solid.

[0634] 1 H NMR65 (400MHz, CDCl3) δ5.79 (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), 1.6 3-1.58(m, 2H), 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).

[0635] Synthesize 66

[0636]

[0637] 10% Pd / C (wet weight, 300 mg) was added to a solution of 65 (220 mg, 0.455 mmol) in THF (15 mL). The mixture was degassed and purged three times with H2. The mixture was stirred at 15 °C for 18 hours under a hydrogen balloon (15 psi). The reaction mixture was filtered through a Celite pad and the pad was washed with THF (4 x 5 mL). The combined organic solutions were concentrated to give 66 (210 mg, crude), which was a solid.

[0638] LCMS 66Rt=5.692min in 7.0min chromatogram, 30-90AB_7MIN_220&254_E, (Column: Ultimate C18 2.1*30mm, 3um; Mobile phase: A: Water (4L) + TFA (1.5mL) B: Acetonitrile (4L) + TFA (0.75mL); Gradient: 30%-90% B over 6min, followed by 0.5min at 90%, then 0.5min at 30% B; Flow rate: 0.8mL / min; Wavelength: UV 220nm, 254nm; Oven temperature: 50℃; MS ionization: ESI; Detector: PDA, ELSD), purity 100%, MS ESI calculated value C 33 H 53 [M+H-2H2O] + 449, measured value 449.

[0639] SFC 66 peak 1: Rt = 6.184 min and peak 2 Rt = 6.969 min in 10 min chromatogram, 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 in 5 min, followed by 2.5 min at 40%, then 2.5 min at 5% B Flow rate: 2.5 mL / min Column temperature: 35℃").

[0640] Synthesize U6477 and U6478

[0641]

[0642] 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; hold time (min): 60 mL / min; injection: 200), yielding U6477 (peak 1, 56 mg, 27%), which was a solid, and U6478 (peak 2, 30 mg, 14%), which was also a solid. Based on the characteristic HNMR of compounds 82 and U6429, the stereochemistry of C7 was assigned to: a) the 7-α-H isomer, where H-6 is a singlet in the high field; b) the 7-β-H isomer, where H-6 is a doublet in the low field.

[0643] U6477

[0644] 1H NMR (400MHz, CDCl3) δ5.79 (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).

[0645] LCMS Rt = 1.490 min in 2.0 min chromatogram, 30-90 AB_2 MIN_E, purity 98.839%, MS ESI calculated value C 33 H 53 [M+H-2H2O] + 449, measured value 449.

[0646] SFC Rt = 6.292 min in 10 min chromatogram, AD_3_EtOH_DEA_5_40_25 mL, 100% de.

[0647] U6478

[0648] 1 H NMR (400MHz, CDCl3) δ5.03 (s, 1H), 2.50-2.42 (m, 1H), 2.05-1.95 (m, 2H), 1.94-1.6 0 (m, 6H), 1.55-1.25 (m, 15H), 1.24-1.05 (m, 12H), 1.03-0.85 (m, 16H), 0.68 (s, 3H).

[0649] LCMS Rt = 1.568 min in 2.0 min chromatogram, 30-90 AB_2MIN_E, purity 100%, MS ESI calculated value C 33 H 53 [M+H-2H2O] + 449, measured value 449.

[0650] SFC Rt = 7.066 min in 10 min chromatogram, AD_3_EtOH_DEA_5_40_25 mL, 95% de.

[0651] Example 6: Synthesis of U6472 and U6473

[0652]

[0653] Overview:

[0654]

[0655] The synthesis of 71 can be seen in Example 3 of this paper.

[0656] Synthesis 72

[0657]

[0658] To a solution of 71 (4 g, 8.76 mmol) in ethyl acetate (200 mL), tert-butyl hydroperoxide (8.74 mL, 52.5 mmol, 6 M in decane) was added. The suspension was stirred under a nitrogen atmosphere for 30 min, and then manganese(III) acetate dihydrate (702 mg, 2.62 mmol) was added in a single batch. After stirring at 30 °C for 48 hours, the mixture was quenched with Na₂SO₃ (200 mL) and extracted with THF (2 x 100 mL). The combined organic matter was washed with Na₂SO₃ (200 mL) and brine (200 mL), dried over Na₂SO₄, filtered, and concentrated to obtain a residue, which was then ground through MeCN (60 mL) to obtain pure 72 (800 mg) as a solid.

[0659] 1 H NMR 72(400MHz, CDCl3) δ5.69-5.64(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), 1.63-1.58 (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).

[0660] Synthesis 73

[0661]

[0662] At -40°C, a solution of 72 (800 mg, 1.69 mmol) in THF (50 mL) was added dropwise to a solution of TMSCH2Li (18.3 mL, 8.45 mmol, 0.46 M in hexane) in THF (20 mL). After addition, the resulting mixture was heated to 30°C and stirred for 16 hours. The mixture was quenched with HCl (2 M, 100 mL) and extracted with EtOAc (2 x 80 mL). The combined organic phases were washed with saturated NaHCO3 (100 mL), dried over Na2SO4, filtered, concentrated, and purified by combi-flash (0-20% EtOAc in PE) to give 73 (350 mg, 44%) as a solid.

[0663] 1 H NMR 73(400MHz, CDCl3) δ5.81-5.76(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), 1.94-1.6 8(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).

[0664] Synthetic 74

[0665]

[0666] Pd / C (350 mg, wet weight) was added to a solution of 73 (350 mg, 0.746 mmol) in THF (30 mL). The mixture was hydrogenated at 15 Psi, 30 °C for 16 hours. The mixture was filtered. The filter cake was washed with THF (2 x 10 mL). The combined filtrate was concentrated and purified by combi-flash (0-20% EtOAc in PE) to give pure 74 (200 mg, 57%) as a solid.

[0667] SFC 74 - Peak 1: Rt = 3.343 min and Peak 2 Rt = 4.297 min in 10 min chromatogram, 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 min followed by 40% for 2.5 min, then 5% B for 2.5 min; Flow rate: 2.5 mL / min; Column temperature: 35℃)

[0668] Synthesize U6472 and U6473

[0669]

[0670] 200 mg of 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, 29% yield, peak 1) and U6473 (43 mg, 22% yield, peak 2), both in solid form. Based on the characteristic HNMR of compounds 82 and U6479, the stereochemistry of C7 was assigned as: a) 7-α-H isomer, with H-6 as a singlet in the high field; b) 7-β-H isomer, with H-6 as a doublet in the low field.

[0671] U6472

[0672] 1 H NMR (400MHz, CDCl3) δ5.35-5.30(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), 1.35-1.24 (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).

[0673] LCMS Rt = 1.240 min in 2.0 min chromatographic medium, 30-90 AB_E, purity 100%, MS ESI calculated value C 28 H 44 F3O[M+H-H2O] + 453, measured value 453.

[0674] SFC Rt = 3.357 min in 10 min chromatogram, AD_3_EtOH_DEA_5_40_25 mL, 99.72% de.

[0675] U6473

[0676] 1 H NMR (400MHz, CDCl3) δ5.06-5.00 (m, 1H), 2.42-2.34 (m, 1H), 2.03-1.95 (m, 2H), 1.87-1.65 (m, 7 H), 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).

[0677] LCMS Rt = 1.246 min in 2.0 min chromatographic medium, 30-90 AB_E, purity 100%, MS ESI calculated value C 28 H 44 F3O[M+H-H2O] + 453, measured value 453.

[0678] SFC Rt = 4.300 min in 10 min chromatogram, AD_3_EtOH_DEA_5_40_25 mL, 99.52% de.

[0679] Example 7: Synthesis of U6450

[0680]

[0681] The synthesis of U6461 can be seen in Example 11 of this document.

[0682] Synthetic 82

[0683]

[0684] At -70°C, K-selectride (1.16 mL, 1.16 mmol 1M in THF) was added dropwise to a solution of U6461 (100 mg, 0.232 mmol) in THF (5 mL). After addition, the mixture was warmed to 0°C and stirred at that temperature for 1 h. The mixture was quenched with saturated NH4Cl (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine (2 x 20 mL), dried over Na2SO4, filtered, concentrated, and purified by combi-flash (0-60% EtOAc in PE) to give 60 mg of impure 82, which was a solid and used directly in the next step. The stereochemistry of C7 is assigned according to the literature (Synthesis, 1987, 1002) and compared with compound U6429, based on a) the 7-α-H isomer, where H-6 is a singlet in the high field; b) the 7-β-H isomer, where H-6 is a doublet in the low field.

[0685] Synthetic U6450

[0686]

[0687] 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: 6 0mL ( / min), yielded 82 (70 mg, 50%), which was a solid.

[0688] 1 H NMR U6450 (400MHz, CDCl3) δ5.58-5.52 (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).

[0689] LCMS U6450 Rt = 1.108 min in 2.0 min chromatogram, 30-90 AB_E, purity 100%, MS ESI calculated value C 28 H 45 O[M+H-2H2O] + 397, measured value 397.

[0690] Example 8: Synthesis of U6437 and U6438

[0691]

[0692] Overview:

[0693]

[0694] The synthesis of U6461 can be seen in Example 11 of this document.

[0695] Synthetic 91

[0696]

[0697] MeLi (2.17 mL, 3.48 mmol) was added to a solution of U6461 (300 mg, 0.696 mmol) in THF (20 mL) at 0 °C and N2. The mixture was stirred at 15 °C for 10 min and quenched with saturated NH4Cl (30 mL). The reaction mixture was extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with saturated NH4Cl (50 mL), dried over Na2SO4, filtered, concentrated, and purified by combi-flash (0-50% EtOAc in PE) to give 91 (250 mg, 81%) as a solid.

[0698] Synthesize U6437 and U6438

[0699]

[0700] 160 mg of 91 was purified by SFC (column: AD (250 mm * 30 mm, 5 μm)), gradient: 50-50. ％ B( A＝0.05％ NH3 / H2O, B=MeOH U6437 (peak 1, 80 mg, 50%) and U6438 (peak 2, 60 mg, 38%) were obtained, which were solids.

[0701] U6437

[0702] 1 H NMR (400MHz, CDCl3) δ5.16-5.13 (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, 7H), 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).

[0703] LCMS Rt = 1.161 min in 2.0 min chromatogram, 30-90 AB_E, purity 100%, MS ESI calculated value C 29 H 47 O[M+H-2H2O] + 411, measured value 411.

[0704] SFC Rt = 4.266 min in 8 min chromatogram, 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).

[0705] Gradient: 5%-40% B over 4.5 min, with 40% B sustained for 2.5 min, then 5% B sustained for 1 min.

[0706] Flow rate: 2.8 mL / min; column temperature: 40 °C; 100% de.

[0707] U6438

[0708] 1H NMR (400MHz, CDCl3) δ5.19-5.16 (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).

[0709] LCMS Rt = 1.162 min in 2.0 min chromatogram, 30-90 AB_E, purity 99.5%, MS ESI calculated value C 29 H 47 O[M+H-2H2O] + 411, measured value 411.

[0710] SFC Rt = 5.815 min in 8 min chromatogram, 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)

[0711] Gradient: 5%-40% B over 4.5 minutes, with 40% B sustained for 2.5 minutes, followed by 5% B sustained for 1 minute.

[0712] Flow rate: 2.8 mL / min; column temperature: 40 °C; 98% de.

[0713] The structure of the compound was confirmed by X-ray diffraction.

[0714] Example 9: Synthesis of U6410

[0715]

[0716] Overview:

[0717]

[0718] The synthesis of U6461 can be seen in Example 11 of this document.

[0719] Synthetic U6410

[0720]

[0721] Pd(OH)₂ (600 mg, anhydrous) was added to a solution of U6461 (300 mg, 0.696 mmol) in MeOH (50 mL). The mixture was stirred at 50 Psi and 50 °C for 48 hours. The mixture was filtered, concentrated, and purified by combi-flash (0-50% EtOAc in PE) to give U6410 (35 mg, 12%) as a solid.

[0722] 1 H NMR (400MHz, CDCl3) δ2.39-2.29(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).

[0723] LCMS-Rt = 1.029 min in 2.0 min chromatogram, 30-90 AB_E, purity 100%, MS ESI calculated value C 28 H 47 O2[M+H-H2O] + 415, measured value 415.

[0724] Example 10: Synthesis of U6408 and U6409

[0725]

[0726] Overview:

[0727]

[0728] The synthesis of U6461 can be seen in Example 11 of this document.

[0729] Synthesis 1101

[0730]

[0731] t-BuOK (389 mg, 3.48 mmol) was added to a suspension of bromo(methyl)triphenylphosphine (1.24 g, 3.48 mmol) in THF (45 mL). The mixture was stirred at 50 °C under N2 for 30 min. 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 h. The mixture was quenched with saturated NH4Cl (50 mL) and extracted with EtOAc (3 x 15 mL). The combined organic phases were dried over Na2SO4, filtered, concentrated, and purified by combi-flash (0-30% EtOAc in PE) to give the desired product (72 mg, 24%) as a solid.

[0732] 1 H NMR (400MHz, CDCl3) δ5.80-5.75 (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).

[0733] Synthesis 1102

[0734]

[0735] Pd / C (wet weight, 150 mg) was added to a solution of 1101 (72 mg, 0.167 mmol) in THF (5 mL). The mixture was stirred at 15 °C and 15 Psi for 12 hours. The mixture was filtered, concentrated, and purified by combi-flash (0-10% EtOAc in PE) to give impure 1102 (50 mg, 69%) as a solid.

[0736] Synthesize U6408 and U6409

[0737]

[0738] 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), yielding U6408 (peak 1, 5 mg, 10%) and U6409 (peak 2, 7 mg, 14%), both in solid form. Based on the characteristic HNMR of compounds 82 and U6429, the stereochemistry of C7 was assigned to: a) the 7-α-H isomer, with H-6 as a singlet in the high field; b) the 7-β-H isomer, with H-6 as a doublet in the low field.

[0739] U6408

[0740] 1 H NMR (400MHz, CDCl3) δ5.33-5.28(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) , 1.52-1.42(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).

[0741] LCMS Rt = 1.245 min in 2.0 min chromatogram, 30-90 AB_E, purity 100%, MS ESI calculated value C 29 H 47 [M+H-2H2O] + 395, measured value 395.

[0742] SFC Rt = 4.245 min in 10 min chromatography, column: ChiralPak AD-3 150×4.6 mm ID, 3 μm mobile phase: A: CO2 B: ethanol (0.05% DEA) gradient: 5%-40% B in 5.5 min, followed by 3 min at 40% B, then 1.5 min at 5% B flow rate: 2.5 mL / min column temperature: 40 °C, 100% DEA.

[0743] U6409

[0744] 1H NMR (400MHz, CDCl3) δ5.04-4.99 (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).

[0745] LCMS Rt = 1.253 min, in a 2.0 min chromatogram, 30-90 AB_E, purity 100%, MS ESI calculated value C 29 H 47 [M+H-2H2O] + 395, measured value 395.

[0746] SFC Rt = 4.967 min, in 10 min chromatography, column: ChiralPak AD-3 150×4.6 mm ID, 3 μm; mobile phase: A: CO2, B: ethanol (0.05% DEA); gradient: 5%-40% B over 5.5 min, followed by 3 min at 40%, then 1.5 min at 5% B; flow rate: 2.5 mL / min; column temperature: 40 °C, 100% DEA.

[0747] Example 11: Synthesis of U6461, U6429, and U6479

[0748]

[0749] Overview:

[0750]

[0751] The synthesis of 1201 can be seen in Example 4 of this paper.

[0752] Synthetic 1202

[0753]

[0754] At 0 °C, MeLi (111 mL, 178 mmol, 1.6 M in diethyl ether) was added dropwise to a solution of impure 1201 (14.9 g, 35.7 mmol) in THF (600 mL). After stirring at 15 °C for 30 min, the mixture was quenched with saturated NH4Cl (500 mL) and extracted with EtOAc (3 x 200 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated to give a crude residue, which was ground with MeCN (300 mL) to give 11 g of crude product as a solid. The crude product was recrystallized from EtOAc (300 mL) to give 1202 (9 g, 80% purity, 49%) as a solid.

[0755] 1 H NMR 1202 (400MHz, CDCl3) δ5.28-5.25(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), 1.38-1.28 (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).

[0756] Synthetic U6461

[0757]

[0758] Molecular sieve (10 g) and tert-butyl hydroperoxide (11.9 mL, 71.4 mmol, 6 M in decane) were added to a solution of 1202 (5 g, 11.9 mmol) in ethyl acetate (300 mL). The suspension was stirred under nitrogen atmosphere for 30 min, and then manganese(III) acetate dihydrate (956 mg, 3.57 mmol) was added in one batch. The reaction mixture was stirred at 15 °C for 48 h. The solid was filtered off. The filtrate was washed with Na₂SO₃ (200 mL) and brine (200 mL) and dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0–15% EtOAc in DCM) to give impure U6461 (2 g, 40%) as a solid. 100 mg of this solid was recrystallized from MeCN (30 mL) at 90 °C to give pure U6461 (34 mg, 34%) as a solid.

[0759] 1H NMR (400MHz, CDCl3) δ5.67-5.64 (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).

[0760] LCMS Rt = 1.059 min in 2.0 min chromatography, 30-90 AB, purity 100%, MS ESI calculated value C 28 H 47 O3[M+H] + 431, measured value 431.

[0761] Synthetic U6429

[0762]

[0763] CeCl3 (857 mg, 3.48 mmol) was added to a solution of U6461 (500 mg, 1.16 mmol) in MeOH (30 mL). After stirring at 15 °C for 30 min, NaBH4 (197 mg, 5.80 mmol) was added in portions. The reaction mixture was stirred at 15 °C for 30 min. The mixture was quenched with saturated NH4Cl (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phases were washed with brine (2 x 100 mL), dried over Na2SO4, filtered, and concentrated to give 470 mg of crude product, which was recrystallized from MeCN (100 mL) to give U6429 (370 mg, 74%) as a solid. The stereochemistry of C7 was assigned according to the literature (Synthesis, 1987, 1002) and compared with compound 82, which is based on a) the 7-α-H isomer, in which H-6 is a singlet in the high field; b) the 7-β-H isomer, in which H-6 is a doublet in the low field.

[0764] 1H NMR (400MHz, CDCl3) δ5.25-5.22(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).

[0765] LCMS Rt = 0.999 min, in a 2.0 min chromatogram, 30-90 AB_E, purity 100%, MS ESI calculated value C 28 H 45 O[M+H-2H2O] + The measured value was 397. The structure of this compound was confirmed by X-ray diffraction.

[0766] Synthetic U6479

[0767]

[0768] Pd(OH)₂ (200 mg, anhydrous) was added to a solution of U6429 (100 mg, 0.231 mmol) in MeOH (30 mL). The mixture was stirred at 50 °C in H₂ (50 Psi) for 48 hours. The mixture was filtered, concentrated, and purified by combi-flash (0-50% EtOAc in PE) to give U6479 (23 mg, 23%) as a solid.

[0769] 1 H NMR (400MHz, CDCl3) δ3.44-3.29 (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).

[0770] LCMS Rt = 1.010 min, in a 2.0 min chromatogram, 30-90 AB_E, purity 100%, MS ESI calculated value C 28 H 45 [M+H-3H2O]+ 381, measured value 381.

[0771] Example 12: EC 50 and E Max data

[0772] Automated Patch Clamp System (QPatch HTX)

[0773] In this study, HEK293 cells stably transfected with glutamate-activated GRIN1 / 2A subtype channels were used together with the second-maximum NMDA concentration (300 μM NMDA, co-administered with 8 μM glycine) to investigate the negative allosteric regulation of the test compounds.

[0774] Cell culture

[0775] Typically, cells are passaged at approximately 80% to 90% confluence. For electrophysiological measurements, cells are harvested from sterile culture flasks containing complete culture medium at approximately 80% to 90% confluence. Cells are transferred as a PBS suspension to a QPatch 16X or QPatch HTX system and then directly to a centrifuge / washer.

[0776] Standard laboratory conditions: Cells were cultured at 37°C in a humid atmosphere containing 5% CO2 (relative humidity of approximately 95%).

[0777] Culture medium: Cells were continuously maintained and passaged in sterile culture flasks containing a 1:1 mixture of Dulbecco modified Eagle medium and nutrient mixture F-12 (D-MEM / F-121x, liquid, containing L-glutamine), the 1:1 mixture being supplemented with 10% fetal bovine serum, 1% penicillin / streptomycin solution and 50 μM AP-5 inhibitor.

[0778] Antibiotics: The complete culture medium, as described above, was supplemented with 100 μg / mL hygromycin, 15 μg / mL cyprodinil, and 1 μg / mL puromycin.

[0779] Expression induction: Add 2.5 μg / mL tetracycline 24 hours before the start of the experiment.

[0780] Dosage Formulation

[0781] Dosage levels are based on the provided test compound. Add the medium to achieve a stock concentration of 10 mM (stored at -10°C to 30°C). Prepare another stock solution of 1.0 mM in DMSO. Record detailed information on stock solution use (thawing, dosage formulation) in the raw data. The time period for stock solution use is detailed in the report.

[0782] Test compound concentration

[0783] Dosage levels are based on the provided test compound. Add the medium to achieve a stock concentration of 10 mM (stored at -10°C to 30°C). Prepare another stock solution of 1.0 mM in DMSO. Record detailed information on stock solution use (thawing, dosage formulation) in the raw data. The time period for stock solution use is detailed in the report.

[0784] One of the test concentrations was 1.0 μM.

[0785] All test solutions were prepared as follows: stock solutions were diluted shortly before electrophysiological experiments with either a magnesium-free bath or a magnesium-free bath containing NMDA (300 μM) and glycine (8.0 μM), and kept at room temperature (19°C–30°C) before use. 0.1% DMSO was used as the medium.

[0786] Preparation frequency: For each test concentration, a fresh test compound solution is prepared daily.

[0787] Stability of dosage formulations: All preparation times are recorded in the raw data. Any observations regarding the instability of the test compounds are mentioned in the raw data.

[0788] Storage of the dosage form: On the day of the experiment, the dosage form should be kept at room temperature (19°C to 30°C) before use.

[0789] bath gel

[0790] To prepare for the experiment and form a gigaohm seal, the following standard bath solution was used:

[0791] 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

[0792] The 1x bath solution was prepared by diluting a glucose-free 10x bath solution and a 100x glucose-containing solution with water at least every 7 days. Both stock solutions were prepared prior to 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). The batch numbers of the bath solutions used in the experiments are recorded in the raw data. When in use, the 1x bath solution was maintained at room temperature (19°C to 30°C). When not in use, the 1x bath solution was stored at 1°C to 9°C.

[0793] After forming a gigabit seal, use the following magnesium-free bath solution:

[0794] 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

[0795] Prepare a 1x solution from the Mg-free bath and store it at 1°C to 9°C. Prepare the solution fresh at least every 10 days.

[0796] Intracellular solution

[0797] The 1x intracellular solution was thawed daily from a frozen 1x intracellular solution, which had been prepared, aliquoted, and stored at -10°C to -30°C prior to the start of the experiments in this study. When used, the 1x intracellular solution was maintained at room temperature (19°C to 30°C). Remaining 1x intracellular solution was stored in a freezer (1°C to 9°C). The 1x intracellular solution comprised the components listed below:

[0798] Potassium chloride: 130 mM; Magnesium chloride: 1 mM; Mg-ATP: 5 mM; HEPES: 10 mM; EGTA: 5 mM; pH (KOH): 7.2

[0799] Cell treatment

[0800] For this study, cells were continuously perfused with NMDA / glycine, the test compound, or the test compound / NMDA / glycine.

[0801] In each case, perform a pre-wash step with the test compound for at least 30 seconds between applications. See Table A below for details.

[0802] Each experimental type was analyzed in at least n = 3 isolated cells. NMDA and glycine stock solutions were prepared prior to the start of the experiments in this study and stored frozen (-10°C to -30°C) until the day of the experiment. The frozen stock solutions were thawed and diluted shortly before the start of the electrophysiological experiments.

[0803] Control: The effects of the mediator (0.1% DMSO) and D-(-)-2-amino-5-phosphonovalerate (AP-5) (100 μM) were measured in three cells every week to ensure successful expression of the NMDA receptor.

[0804] Prior to the start of the experiments in this study, a 50 mM AP-5 stock solution was prepared, aliquoted, and frozen (from -10°C to -30°C) until the day of the experiments. Shortly before the start of the electrophysiological experiments, the frozen stock solution was thawed and then diluted in a Mg-free bath containing NMDA (300 μM) and glycine (8.0 μM) to obtain a final perfusion concentration of 100 μM.

[0805] Experimental steps

[0806] Cells were transferred as a suspension in serum-free medium to the QPatch HTX system and kept in the cell storage tank / stirrer during the experiment. All solutions applied to the cells, including intracellular solutions, were kept at room temperature (19°C to 30°C).

[0807] During the sealing process, the standard bath solution described above was used. All solutions applied to the cells, including pipette solutions, were maintained at room temperature (19°C to 30°C). After a gigaohmic seal was formed between the patch electrode and the transfected single HEK293 cell, only a Mg-free bath solution was infused and the cell membrane was ruptured to ensure electrical ingress into the cells (whole-cell patch configuration). The inward current was measured 5 seconds after applying 300 μM NMDA (and 8.0 μM glycine) to the patch-clamp cells. Throughout the experiment, the cell was voltage-clamped at a holding potential of -80 mV.

[0808] To analyze the test compound, NMDA receptors were stimulated with 300 μM NMDA and 8.0 μM glycine, along with the test compound described below. A thirty-second pre-wash step was performed using the test compound between applications.

[0809] Table A: Application schemes; use dependence of test compounds

[0810]

[0811]

[0812] Table B: Application Plan; Control Trial

[0813]

[0814] The results are recorded in Table 1:

[0815] Table 1

[0816]

[0817]

[0818]

[0819] abbreviation

[0820] PCC: Pyridinium chlorochromate; t-BuOK: Potassium tert-butoxide; 9-BBN: 9-boronabicyclo[3.3.1]nonane; Pd(t-Bu3P)2: Bis(tri-tert-butylphosphine)palladium(0); AcCl: Acetyl chloride; i-PrMgCl: Magnesium isopropyl chloride; TBSCl: Tert-butyl(chloro)dimethylsilane; (i-PrO)4Ti: Tetraisopropoxide titanium; BHT: 2,6-Di-tert-butyl-4-methylphenol salt; 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: Dys-Martin reagent; EtMgBr: Ethyl magnesium bromide; EtOAc: Ethyl acetate; TEA: Triethylamine; AlaOH: Alanine; Boc: Tert-butylcarbonyl. Py: Pyridine; TBAF: Tetra-n-butylammonium fluoride; THF: Tetrahydrofuran; TBS: Tert-butyldimethylsilyl; TMS: Trimethylsilyl; TMSCF3: (Trifluoromethyl)trimethylsilane; Ts: p-Toluenesulfonyl; Bu: Butyl; Ti(OiPr)4: Tetraisopropoxytitanium; LAH: Lithium aluminum hydride; LDA: Lithium diisopropylaminodimethyl; LiOH.H2O: Lithium hydroxide hydrate; MAD: Methylaluminum bis(2,6-di-tert-butyl-4-methylphenol); MeCN: Acetonitrile; NBS: N-bromosuccinimide; Na2SO4: Sodium sulfate; Na2S2O3: Sodium thiosulfate; PE: Petroleum ether; MeCN: Acetonitrile; MeOH: Methanol; Boc: Tert-butoxycarbonyl; MTBE: Methyl tert-butyl ether; K-selectride: Potassium tris(sec-butyl)borohydride.

[0821] Other implementation plans

[0822] In the claims, articles such as “a,” “the,” and “the” may indicate one or more members unless otherwise stated or obvious from the context. A claim or specification including “or” among one or more members of the group is considered satisfied if one, more than one, or all members of the group are present, used, or otherwise associated with a given product or process, unless otherwise stated or obvious from the context. The invention includes embodiments in which exactly one member of the group is present in a given product or process, and is used or otherwise associated with the given product or process. The invention includes embodiments in which more than one or all members of the group are present, used, or associated with a given product or process.

[0823] Furthermore, this invention includes all variations, combinations, and substitutions, wherein one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims are introduced into another claim. For example, any claim dependent on another claim may be modified to include one or more limitations found in any other claim dependent on the same base claim. Where elements are presented in list form, for example, in Markush format, each subgroup of elements is also disclosed, and any element may be removed from the group. It should be understood that, in general, where the invention or an aspect of the invention is referred to as including specific elements and / or features, certain embodiments of the invention or aspects of the invention include or are substantially composed of these elements and / or features. For simplicity, these embodiments are not specifically described herein. It should also be noted that the terms “comprising” and “containing” are intended to be open and allow for the inclusion of additional elements or steps. Where a range is given, endpoints are included. Furthermore, unless otherwise indicated from the context and understanding of one of ordinary skill in the art or otherwise apparent, values ​​expressed as ranges may present any specific value or subrange up to one-tenth of the lower limit of the range in different embodiments of the invention, unless the context expressly specifies otherwise.

[0824] This application relates to various granted patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of any conflict between any incorporated references and this specification, this specification shall prevail. Furthermore, any particular embodiment of the invention falling within the prior art may be expressly excluded from any one or more claims. Because such embodiments are considered to be known to those skilled in the art, they may be excluded even if not expressly stated herein. Any particular embodiment of the invention may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0825] Those skilled in the art will recognize or be able to determine many equivalents of the specific embodiments described herein using no more than conventional experiments. The scope of the embodiments of the invention described herein is not intended to be limited to the above description, but is set forth in the appended claims. Those skilled in the art will understand that various changes and modifications can be made to this specification without departing from the spirit or scope of the invention as defined in the following claims.

[0826] Specifically, this application relates to the following technical solutions:

[0827] 1. Compound of formula (A):

[0828]

[0829] Or its pharmaceutically acceptable salt, wherein:

[0830] R1A and R1B are each independently hydrogen, substituted or unsubstituted alkyl, carbocyclic, heterocyclic, aryl or heteroaryl, or R1A and R1B together with the carbon atoms to which they are attached form a 3-8 membered ring.

[0831] n is 1 or 2;

[0832] R2A and R2B are each independently hydrogen, halogen, –ORC, alkyl, alkenyl, alkynyl, aryl or heteroaryl, wherein RC is hydrogen or alkyl or R2A and R2B together with the carbon atom to which they are attached form an oxo group, wherein R2A and R2B are not both hydrogen.

[0833] R3 is hydrogen, alkyl, alkenyl, ynyl or –ORA, where RA is alkyl;

[0834] R4 is absent or is hydrogen; and

[0835] Represents a single bond or a double bond, where when one When it is a double bond, then the other one... For a single bond; when two When both are single bonds, then R4 is hydrogen; and when one is a single bond... When it is a double bond, R4 does not exist.

[0836] 2. Based on the compound in 1, where n is 1.

[0837] 3. Based on the compound in 1, where n is 2.

[0838] 4. According to the compound in 1, when R1A, R3, and R4 are hydrogen atoms and R1B is an unsubstituted isopropyl group, then R2A and R2B, together with the carbon atoms they are attached to, do not form oxo groups; and

[0839] When R4 is absent, R3 is hydrogen, and R1A and R1B are –CH3, then R2A is not –CH3 and R2B is not –OH.

[0840] 5. According to the compound in 1, when R4 is absent, R2A is –OH, R2B is hydrogen or –CF3, and R1A and R1B are –CH3, then R3 is not hydrogen; and

[0841] When R1A and R1B are –CH3 and R3 is hydrogen, then R2A and R2B together with the carbon atoms they are attached to do not form oxo groups.

[0842] 6. According to 1, the compound of formula (A) is a compound of formula (AI):

[0843]

[0844] 7. According to 1, the compound of formula (A) is a compound of formula (A-II):

[0845]

[0846] 8. According to 1, the compound of formula (A) is a compound of formula (A-III):

[0847]

[0848] 9. According to 1, the compound of formula (A) is a compound of formula (A-IV), (AV), or (A-VI):

[0849]

[0850] Where R2C is hydrogen or alkyl and R3 is alkyl, alkenyl, ynyl or –ORA, where RA is alkyl.

[0851] 10. Compounds according to 1, wherein compound (A) is a compound of formula (A-VII), (A-VIII), or (A-IX):

[0852]

[0853] R3 is alkyl, alkenyl, ynyl or –ORA, where RA is alkyl.

[0854] 11. According to the compounds in 1, the compound of formula (A) is a compound of formula (AX):

[0855]

[0856] R3 is an alkyl, alkenyl, alkynyl or –ORA, where RA is an alkyl.

[0857] 12. According to 1, the compound of formula (A) is a compound of formula (A-XII).

[0858]

[0859] Where R' is an alkyl or –ORA, where RA is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5 or 6; and m is 0, 1, 2 or 3.

[0860] 13. A compound of any one of 1-12, wherein R4 is absent, one of R2A and R2B is –OH and R3 is not hydrogen.

[0861] 14. A compound of any one of 1-11, wherein R1A and R1B are each independently an unsubstituted or substituted alkyl group.

[0862] 15. The compound according to 14, wherein R1A and R1B are each independently selected from alkyl halogen, alkoxyalkyl, –CH3, –CH2CH3, –CH(CH3)2, –CF3 and –CH2OCH3.

[0863] 16. A compound of any one of 1-11, wherein R1A and R1B are each independently substituted alkyl groups.

[0864] 17. The compound according to 16, wherein R1A and R1B are each independently a haloalkyl group.

[0865] 18. A compound of any one of 1-11, wherein R1A is –CF3 or –CH2OCH3.

[0866] 19. A compound of any one of 1-11, wherein R1A and R1B are unsubstituted or substituted alkyl groups.

[0867] 20. A compound of any one of 1-11, wherein R1A and R1B are –CH3.

[0868] 21. A compound of any one of 1-11, wherein R1A and R1B together with the carbon atoms to which they are attached form a 3- to 8-membered ring.

[0869] 22. A compound of any one of 1-11, wherein R1A is hydrogen and R1B is alkyl, carbocyclic, heterocyclic, aryl or heteroaryl.

[0870] 23. A compound of any one of 1-11, wherein R1A is a substituted alkyl or an unsubstituted C2-C6 alkyl and R1B is a substituted or unsubstituted C1-C6 alkyl.

[0871] 24. A compound of any one of 1-8 or 13, wherein R2A and R2B are each independently a substituted or unsubstituted alkyl group.

[0872] 25. A compound of any one of 1-8 or 12, wherein R2A and R2B are each independently –F.

[0873] 26. A compound of any one of 1-8 or 12, wherein R2A and R2B are –CH3 and R3 is alkyl, alkenyl, alkynyl or –ORA, wherein RA is alkyl.

[0874] 27. A compound of any one of 1-12, wherein R3 is a substituted or unsubstituted alkyl, alkenyl, alkynyl or –ORA, wherein RA is an alkyl group.

[0875] 28. A compound of any one of 1-12, wherein R3 is a substituted or unsubstituted alkyl group.

[0876] 29. A compound of any one of 1-8 or 12, wherein R2A and R2B are each independently hydrogen and R3 is a substituted or unsubstituted alkyl group.

[0877] 30. A pharmaceutical composition comprising the compound of 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier thereof.

[0878] 31. A method for inducing sedation or anesthesia, comprising administering to a subject an effective amount of the compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0879] 32. Methods of treating or preventing the conditions described herein, including administering to a subject in need an effective amount of the compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0880] 33. According to the method of 32, the condition is a gastrointestinal (GI) condition, constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, a structural condition affecting the gastrointestinal tract, anal condition, hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas, colonic polyps, cancer, or colitis.

[0881] 34. According to the method in 32, the condition described is inflammatory bowel disease.

[0882] 35. According to the method of 32, the condition is cancer, diabetes or sterol synthesis disorder.

[0883] 36. According to the method in 32, the condition is a metabolic disorder.

[0884] 37. According to the method in 32, the condition described is an autoimmune disease.

[0885] 38. According to the method of 32, the condition is rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and plaque psoriasis.

[0886] 39. A method of treating or preventing CNS-related conditions, comprising administering to a subject in need an effective amount of the compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0887] 40. According to the method of 39, the CNS-related disorders mentioned therein are 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), dissociative disorders, eating disorders, affective disorders (including depression and postpartum depression, bipolar disorder, dysthymia, and suicide), schizophrenia or other psychosis (including affective schizophrenia), sleep disorders (including insomnia), substance-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations in the Shank proteome (Shank3), neurodevelopmental disorders (including Rett syndrome and complex tuberous sclerosis), multiple sclerosis, sterol synthesis disorders, pain (including acute and chronic pain), encephalopathy secondary to medical conditions (including hepatic encephalopathy and anti-NMDA receptor encephalitis), seizures (including status epilepticus and monogenic forms of epilepsy such as Dravet disease), stroke, traumatic brain injury, motor disorders (including Huntington's disease and Parkinson's disease), visual impairment, hearing loss, or tinnitus.

[0888] 41. According to the method of 32, the condition is a sterol synthesis condition.

[0889] 42. Compound of formula (B):

[0890]

[0891] Or its pharmaceutically acceptable salt, wherein:

[0892] R1A and R1B are each independently hydrogen, substituted or unsubstituted alkyl, carbocyclic, heterocyclic, aryl or heteroaryl, or R1A and R1B together with the carbon atoms to which they are attached form a 3-8 membered ring.

[0893] n is 1 or 2;

[0894] R2A and R2B are each independently hydrogen, halogen, –ORC, alkyl, alkenyl, alkynyl, aryl or heteroaryl, wherein RC is hydrogen or alkyl or R2A and R2B together with the carbon atom to which they are attached form an oxo group, wherein R2A and R2B are not both hydrogen.

[0895] R3 is alkyl, alkenyl, alkynyl or –ORA, where RA is alkyl;

[0896] R4 is absent or is hydrogen; and

[0897] Represents a single bond or a double bond, where when one When it is a double bond, then the other one... For a single bond; when two When both are single bonds, then R4 is hydrogen; and when one is a single bond... When it is a double bond, R4 does not exist.

[0898] 43. Based on the compound in 42, where n is 1.

[0899] 44. Based on the compound in 42, where n is 2.

[0900] 45. Based on the compounds in 42, compound (B) is compound (BI):

[0901]

[0902] 46. ​​According to the compound of 42, wherein the compound of formula (B) is a compound of formula (B-II):

[0903]

[0904] 47. According to the compound of 42, wherein the compound of formula (B) is a compound of formula (B-III):

[0905]

[0906] 48. The compound according to 42, wherein the compound of formula (B) is a compound of formula (B-IV), (BV), or (B-VI):

[0907]

[0908] Where R2C is hydrogen or alkyl and R3 is alkyl, alkenyl, ynyl or –ORA, where RA is alkyl.

[0909] 49. According to the compound of 42, wherein the compound of formula (B) is a compound of formula (B-VII), (B-VIII), or (B-IX):

[0910]

[0911] R3 is an alkyl, alkenyl, alkynyl or –ORA, where RA is an alkyl.

[0912] 50. According to the compound of 42, wherein the compound of formula (B) is a compound of formula (BX):

[0913]

[0914] R3 is an alkyl, alkenyl, alkynyl or –ORA, where RA is an alkyl.

[0915] 51. According to the compound of 42, wherein the compound of formula (B) is a compound of formula (B-XII).

[0916]

[0917] Where R' is an alkyl or –ORA, where RA is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5 or 6; and m is 0, 1, 2 or 3.

[0918] 52. A compound according to any one of 42-50, wherein R1A and R1B are each independently an unsubstituted or substituted alkyl group.

[0919] 53. The compound according to 52, wherein R1A and R1B are each independently selected from haloalkyl, alkoxyalkyl, –CH3, –CH2CH3, –CH(CH3)2, –CF3 and –CH2OCH3.

[0920] 54. A compound according to any one of 42-50, wherein R1A and R1B are each independently substituted alkyl groups.

[0921] 55. A compound according to any one of 42-50, wherein R1A and R1B are each independently a haloalkyl group.

[0922] 56. A compound according to any one of 42-50, wherein R1A is –CF3 or –CH2OCH3.

[0923] 57. A compound according to any one of 42-50, wherein R1A and R1B are –CH3.

[0924] 58. A compound according to any one of 42-50, wherein R1A and R1B together with the carbon atoms to which they are attached form a 3- to 8-membered ring.

[0925] 59. A compound according to any one of 42-50, wherein R1A is hydrogen and R1B is alkyl, carbocyclic, heterocyclic, aryl or heteroaryl.

[0926] 60. A compound according to any one of 42-50, wherein R1A is a substituted alkyl or unsubstituted C2-C6 alkyl and R1B is a substituted or unsubstituted C1-C6 alkyl.

[0927] 61. A compound according to any one of 42-50, wherein R2A and R2B are each independently substituted or unsubstituted alkyl groups.

[0928] 62. A compound according to any one of 42-51, wherein R2A and R2B are each independently –F.

[0929] 63. A compound according to any one of 42-51, wherein R2A and R2B are –CH3 and R3 is alkyl, alkenyl, alkynyl or –ORA, wherein RA is alkyl.

[0930] 64. A compound according to any one of 42-51, wherein R3 is a substituted or unsubstituted alkyl, alkenyl, ynyl or –ORA, wherein RA is an alkyl group.

[0931] 65. A compound according to any one of 42-51, wherein R3 is a substituted or unsubstituted alkyl group.

[0932] 66. A compound according to any one of 42-51, wherein R2A and R2B are each independently hydrogen and R3 is a substituted or unsubstituted alkyl group.

[0933] 67. A pharmaceutical composition comprising 42 compounds or pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers.

[0934] 68. A method for inducing sedation or anesthesia, comprising administering to a subject an effective amount of the compound 42 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0935] 69. Methods of treating or preventing the conditions described herein, including administering to a subject in need an effective amount of the compound 42 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0936] 70. According to the method of 69, the condition mentioned is a gastrointestinal (GI) condition, constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, a structural condition affecting the gastrointestinal tract, anal condition, hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas, colonic polyps, cancer, or colitis.

[0937] 71. According to the method in 69, the condition described is inflammatory bowel disease.

[0938] 72. According to the method of 69, the condition is cancer, diabetes or sterol synthesis disorder.

[0939] 73. According to the method of 69, the condition described is a metabolic disorder.

[0940] 74. According to the method in 69, the condition described is an autoimmune disease.

[0941] 75. According to the method of 69, the condition mentioned is rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and plaque psoriasis.

[0942] 76. A method for treating or preventing CNS-related conditions, comprising administering to a subject in need an effective amount of the compound 42 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0943] 77. According to the method of 76, the CNS-related disorders are 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), dissociative disorders, eating disorders, affective disorders (including depression and postpartum depression, bipolar disorder, dysthymia, and suicide), schizophrenia or other psychosis (including affective schizophrenia), sleep disorders (including insomnia), substance-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations in the Shank proteome (Shank3), neurodevelopmental disorders (including Rett syndrome and complex tuberous sclerosis), multiple sclerosis, sterol synthesis disorders, pain (including acute and chronic pain), encephalopathy secondary to medical conditions (including hepatic encephalopathy and anti-NMDA receptor encephalitis), seizures (including status epilepticus and monogenic forms of epilepsy such as Dravet disease), stroke, traumatic brain injury, motor disorders (including Huntington's disease and Parkinson's disease), visual impairment, hearing loss, or tinnitus.

[0944] 78. According to the method of 69, the condition described is a sterol synthesis disorder.

[0945] 79. Compound of formula (I):

[0946]

[0947] Or its pharmaceutically acceptable salt, wherein:

[0948] R1A and R1B are each independently hydrogen, substituted or unsubstituted alkyl, carbocyclic, heterocyclic, aryl or heteroaryl, or

[0949] R1A and R1B together with the carbon atoms they are attached to form 3-8 membered rings;

[0950] R2A and R2B are each independently hydrogen, halogen, –ORC, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, wherein RC is hydrogen or alkyl, or

[0951] R2A and R2B together with the carbon atoms they are attached to form oxo groups, wherein R2A and R2B are not both hydrogen atoms;

[0952] R3 is hydrogen, alkyl, alkenyl, ynyl or –ORA, where RA is alkyl;

[0953] R4 is absent or is hydrogen; and

[0954] Represents a single bond or a double bond, where when one When it is a double bond, then the other one... For a single bond; when two When both are single bonds, then R4 is hydrogen; and when one is a single bond... When it is a double bond, R4 does not exist;

[0955] The premise is that when R1A, R3, and R4 are hydrogen and R1B is an unsubstituted isopropyl group, then R2A and R2B, together with the carbon atoms they are attached to, do not form oxo groups; and

[0956] When R4 is absent, R3 is hydrogen, and R1A and R1B are –CH3, then R2A is not –CH3 and R2B is not –OH.

[0957] 80. According to the compound of 79, wherein R1A, R3 and R4 are hydrogen, R1B is an unsubstituted isopropyl group and R2A and R2B together with the carbon atoms to which they are attached do not form oxo groups.

[0958] 81. Based on the compound in 79, R4 is absent, R3 is hydrogen, R1A and R1B are –CH3, R2A is not –CH3 and R2B is not –OH.

[0959] 82. According to the compound of 79, wherein the compound of formula (I) is a compound of formula (IA):

[0960]

[0961] 83. According to the compound of 79, wherein the compound of formula (I) is a compound of formula (IB):

[0962]

[0963] 84. According to the compound of 79, wherein the compound of formula (I) is a compound of formula (IC):

[0964]

[0965] 85. According to the compound of 79, wherein the compound of formula (I) is a compound of formula (IE), (IF), or (IG):

[0966]

[0967] Where R2C is hydrogen or alkyl and R3 is alkyl, alkenyl, ynyl or –ORA, where RA is alkyl.

[0968] 86. According to the compound of 79, wherein the compound of formula (I) is a compound of formula (IH), (II) or (IJ):

[0969]

[0970]

[0971] R3 is an alkyl, alkenyl, alkynyl or –ORA, where RA is an alkyl.

[0972] 87. According to the compound of 79, wherein the compound of formula (I) is a compound of formula (IK):

[0973]

[0974] R3 is an alkyl, alkenyl, alkynyl or –ORA, where RA is an alkyl.

[0975] 88. According to the compound of 79, wherein the compound of formula (I) is a compound of formula (IM):

[0976]

[0977] Where R' is an alkyl or –ORA, where RA is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5 or 6; and m is 0, 1, 2 or 3.

[0978] 89. A compound according to any one of 79-87, wherein R1A and R1B are each independently an unsubstituted or substituted alkyl group.

[0979] 90. A compound according to any one of 79-87, wherein R1A and R1B are each independently selected from haloalkyl, alkoxyalkyl, –CH3, –CH2CH3, –CH(CH3)2, –CF3 and –CH2OCH3.

[0980] 91. A compound according to any one of 79-87, wherein R1A and R1B are each independently substituted alkyl groups.

[0981] 92. A compound according to any one of 79-87, wherein R1A and R1B are each independently a haloalkyl group.

[0982] 93. A compound according to any one of 79-87, wherein R1A is –CF3 or –CH2OCH3.

[0983] 94. A compound according to any one of 79-87, wherein R1A and R1B are unsubstituted or substituted alkyl groups.

[0984] 95. A compound according to any one of 79-87, wherein R1A and R1B are –CH3.

[0985] 96. A compound according to any one of 79-87, wherein R1A and R1B together with the carbon atoms to which they are attached form a 3- to 8-membered ring.

[0986] 97. A compound according to any one of 79-87, wherein R1A is hydrogen and R1B is alkyl, carbocyclic, heterocyclic, aryl or heteroaryl.

[0987] 98. A compound according to any one of 79-87, wherein R1A is a substituted alkyl or unsubstituted C2-C6 alkyl and R1B is a substituted or unsubstituted C1-C6 alkyl.

[0988] 99. A compound according to any one of 79-88, wherein R2A and R2B are each independently substituted or unsubstituted alkyl groups.

[0989] 100. A compound according to any one of 79-88, wherein R2A and R2B are each independently –F.

[0990] 101. A compound according to any one of 79-88, wherein R2A and R2B are –CH3 and R3 is alkyl, alkenyl, alkynyl or –ORA, wherein RA is alkyl.

[0991] 102. A compound according to any one of 79-88, wherein R2A and R2B are –F.

[0992] 103. A compound according to any one of 79-88, wherein R3 is a substituted or unsubstituted alkyl, alkenyl, alkynyl or –ORA, wherein RA is an alkyl group.

[0993] 104. A compound according to any one of 79-88, wherein R3 is an alkyl, substituted or unsubstituted alkyl group.

[0994] 105. A compound according to any one of 79-88, wherein R2A and R2B are each independently hydrogen and R3 is a substituted or unsubstituted alkyl group.

[0995] 106. A pharmaceutical composition comprising 79 of the compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0996] 107. A method for inducing sedation or anesthesia, comprising administering to a subject an effective amount of the compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0997] 108. Methods of treating or preventing the conditions described herein, including administering to a subject in need an effective amount of the compound 79 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0998] 109. The method of 108, wherein the condition is a gastrointestinal (GI) condition, constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, a structural condition affecting the gastrointestinal tract, anal condition, hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas, colonic polyps, cancer, or colitis.

[0999] Method 110.108, wherein the condition is inflammatory bowel disease.

[1000] The method of 111.108, wherein the condition is cancer, diabetes or a sterol synthesis disorder.

[1001] The method of 112.108, wherein the condition is a metabolic disorder.

[1002] Method 113.108, wherein the condition is an autoimmune disease.

[1003] The method of 114.108, wherein the condition is rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and plaque psoriasis.

[1004] 115. A method of treating or preventing CNS-related conditions, comprising administering to a subject in need an effective amount of the compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[1005] 116. According to the method of 115, the CNS-related disorders are 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), dissociative disorders, eating disorders, mood disorders (including depression or postpartum depression, bipolar disorder, dysthymia, and suicide), schizophrenia or other psychosis (including affective schizophrenia), sleep disorders (including insomnia), substance-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations in the Shank proteome (Shank3)), neurodevelopmental disorders (including Rett syndrome and complex tuberous sclerosis), multiple sclerosis, sterol synthesis disorders, pain (including acute and chronic pain), encephalopathy secondary to medical conditions (including hepatic encephalopathy and anti-NMDA receptor encephalitis), seizures (including status epilepticus and monogenic forms of epilepsy such as Dravet disease), stroke, traumatic brain injury, movement disorders (including Huntington's disease and Parkinson's disease), visual impairment, hearing loss, or tinnitus.

[1006] The method of 117.108, wherein the condition is a sterol synthesis condition.

[1007] 118. Compound of formula (II):

[1008]

[1009] Or its pharmaceutically acceptable salt, wherein:

[1010] R1A and R1B are each independently hydrogen, substituted or unsubstituted alkyl, carbocyclic, heterocyclic, aryl or heteroaryl, or

[1011] R1A and R1B together with the carbon atoms they are attached to form 3-8 membered rings;

[1012] R2A and R2B are each independently hydrogen, halogen, –ORC, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, wherein RC is hydrogen or alkyl, or

[1013] R2A and R2B together with the carbon atoms they are attached to form oxo groups, wherein R2A and R2B are not both hydrogen atoms;

[1014] R3 is hydrogen, alkyl, alkenyl, ynyl or –ORA, where RA is alkyl;

[1015] R4 is absent or is hydrogen; and

[1016] Represents a single bond or a double bond, where when one When it is a double bond, then the other one... For a single bond; when two When all bonds are single bonds, then R4 is hydrogen; and when one bond is single bond... When it is a double bond, R4 does not exist;

[1017] The premise is that when R4 is absent, R2A is –OH, R2B is hydrogen or –CF3, and R1A and R1B are –CH3, then R3 is not hydrogen; and

[1018] When R1A and R1B are –CH3 and R3 is hydrogen, then R2A and R2B together with the carbon atoms they are attached to do not form oxo groups.

[1019] 119. Based on the compound in 118, R4 is absent, one of R2A and R2B is –OH, and R3 is not hydrogen.

[1020] 120. According to the compound of 118, wherein the compound of formula (II) is a compound of formula (II-A):

[1021]

[1022] 121. According to the compound of 118, wherein the compound of formula (II) is a compound of formula (II-B):

[1023]

[1024] 122. According to the compound of 118, wherein the compound of formula (II) is a compound of formula (II-C):

[1025]

[1026] 123. According to the compound of 118, wherein the compound of formula (II) is a compound of formula (II-D):

[1027]

[1028] 124. The compound according to 118, wherein the compound of formula (II) is a compound of formula (II-E), (II-F), or (II-G):

[1029]

[1030] Wherein R2C is hydrogen or a substituted or unsubstituted alkyl group and R3 is an alkyl group, substituted or unsubstituted alkyl group.

[1031] 125. The compound according to 118, wherein the compound of formula (II) is a compound of formula (II-H), (II-I), or (II-J):

[1032]

[1033] R3 is an alkyl, alkenyl, alkynyl or –ORA, where RA is an alkyl.

[1034] 126. According to the compound of 118, wherein the compound of formula (II) is a compound of formula (II-K):

[1035]

[1036] Where R' is an alkyl or –ORA, where RA is hydrogen or alkyl; p is 0, 1, 2, 3, 4, 5 or 6; and m is 0, 1, 2 or 3.

[1037] 127. A compound according to any one of 118-125, wherein R1A and R1B are each independently an unsubstituted or substituted alkyl group.

[1038] 128. A compound according to any one of 118-125, wherein R1A and R1B are independently selected from haloalkyl, alkoxyalkyl, –CH3, –CH2CH3, –CH(CH3)2, –CF3 and –CH2OCH3.

[1039] 129. A compound according to any one of 118-125, wherein R1A and R1B are each independently substituted alkyl groups.

[1040] 130. According to the compound of 129, wherein R1A and R1B are each a haloalkyl group.

[1041] 131. A compound according to any one of 118-125, wherein R1A is –CF3 or –CH2OCH3.

[1042] 132. A compound according to any one of 118-125, wherein R1A and R1B are unsubstituted or substituted alkyl groups.

[1043] 133. A compound according to any one of 118-125, wherein R1A and R1B are –CH3.

[1044] 134. A compound according to any one of 118-125, wherein R1A and R1B together with the carbon atoms to which they are attached form a ring.

[1045] 135. A compound according to any one of 118-125, wherein R1A is hydrogen and R1B is alkyl, carbocyclic, heterocyclic, aryl or heteroaryl.

[1046] 136. A compound according to any one of 118-126, wherein R2A and R2B are each independently substituted or unsubstituted alkyl groups.

[1047] 137. A compound according to any one of 118-126, wherein R3 is an alkyl group, substituted or unsubstituted.

[1048] 138. A compound according to any one of 118-126, wherein R2A and R2B are each independently hydrogen and R3 is a substituted or unsubstituted alkyl group.

[1049] 139. A compound according to any one of 118-126, wherein R2A and R2B are each independently –F.

[1050] 140. A compound according to any one of 118-126, wherein R2A and R2B are –CH3 and R3 is alkyl, alkenyl, alkynyl or –ORA, wherein RA is alkyl.

[1051] 141. A compound according to any one of 118-126, wherein R2A and R2B are –F.

[1052] 142. A compound according to any one of 118-125, wherein R1A is a substituted alkyl or unsubstituted C2-C6 alkyl and R1B is a substituted or unsubstituted C1-C6 alkyl.

[1053] 143. A pharmaceutical composition comprising a compound of 118 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[1054] 144. A method for inducing sedation or anesthesia, comprising administering to a subject an effective amount of the compound 118 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[1055] 145. Methods of treating or preventing the conditions described herein, including administering to a subject in need an effective amount of the compound 118 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[1056] 146. According to the method of 145, the condition is a gastrointestinal (GI) condition, constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, a structural condition affecting the gastrointestinal tract, anal condition, hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas, colonic polyps, cancer, or colitis.

[1057] 147. According to the method of 145, the condition described is inflammatory bowel disease.

[1058] 148. According to the method of 145, the condition is cancer, diabetes or sterol synthesis disorder.

[1059] 149. According to the method of 145, the condition is a metabolic disorder.

[1060] 150. According to the method of 145, the condition described is an autoimmune disease.

[1061] 151. According to the method of 145, the condition is rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and plaque psoriasis.

[1062] 152. A method for treating or preventing CNS-related conditions, comprising administering to a subject in need an effective amount of the compound 118 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[1063] 153. According to the method of 152, the CNS-related disorders mentioned therein are 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), dissociative disorders, eating disorders, affective disorders (including depression and postpartum depression), bipolar disorder, dysthymia, and suicide), schizophrenia or other psychosis (including affective schizophrenia), sleep disorders (including insomnia), substance-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations in the Shank proteome (Shank3)), neurodevelopmental disorders (including Rett syndrome and complex tuberous sclerosis), multiple sclerosis, sterol synthesis disorders, pain (including acute and chronic pain), encephalopathy secondary to medical conditions (including hepatic encephalopathy and anti-NMDA receptor encephalitis), seizures (including status epilepticus and monogenic forms of epilepsy such as Dravet disease), stroke, traumatic brain injury, movement disorders (including Huntington's disease and Parkinson's disease), visual impairment, hearing loss, or tinnitus.

[1064] 154. According to the method of 145, the condition is a sterol synthesis condition.

[1065] 155. Compound of formula (III):

[1066]

[1067] Or its pharmaceutically acceptable salt, wherein:

[1068] R1A and R1B are each substituted or unsubstituted alkyl groups;

[1069] R2A and R2B are each independently hydrogen, ORC, or alkyl, where RC is hydrogen or alkyl, or

[1070] R2A and R2B together with the carbon atoms they are attached to form oxo groups, wherein R2A and R2B are not both hydrogen atoms;

[1071] R3 is an alkyl group;

[1072] R4 is absent or is hydrogen; and

[1073] Represents a single bond or a double bond, where when one When it is a double bond, then the other one... For a single bond; when two When both are single bonds, then R4 is hydrogen; and when one is a single bond... When it is a double bond, R4 does not exist.

[1074] 156. According to the compound in 155, where R1A and R1B are each –CH3.

[1075] 157. According to the compound of 155, R2A and R2B together with the carbon atoms to which they are attached form oxo groups.

[1076] 158. Based on the compound in 155, where R3 is –CH2CH3.

[1077] 159. Based on the compound in 155, where R2A is –OH and R2B is H.

[1078] 160. According to the compound in 155, R2A is –CH3 and R2B is H.

[1079] 161. Based on the compound in 155, where R2A is –OH and R2B is –CH3.

[1080] 162. According to compound 155, where R1A is –CF3.

[1081] 163. A pharmaceutical composition comprising a compound of 155 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[1082] 164. A method for inducing sedation or anesthesia, comprising administering to a subject an effective amount of the compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[1083] 165. Methods of treating or preventing the conditions described herein, including administering to a subject in need an effective amount of the compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[1084] 166. According to the method of 165, the condition mentioned is a gastrointestinal (GI) condition, constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, a structural condition affecting the gastrointestinal tract, anal condition, hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas, colonic polyps, cancer, or colitis.

[1085] 167. According to the method in 165, the condition described is inflammatory bowel disease.

[1086] 168. According to the method of 165, the condition is cancer, diabetes or sterol synthesis disorder.

[1087] 169. According to the method of 165, the condition described is a metabolic disorder.

[1088] 170. According to the method in 165, the condition described is an autoimmune disease.

[1089] 171. According to the method of 165, the condition is rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and plaque psoriasis.

[1090] 172. A method of treating or preventing CNS-related conditions, comprising administering to a subject in need an effective amount of the compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[1091] 173. According to the method of 172, the CNS-related disorders are: 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), dissociative disorders, eating disorders, affective disorders (including depression and postpartum depression), bipolar disorder, dysthymia, and suicide), schizophrenia or other psychosis (including affective schizophrenia), sleep disorders (including insomnia), substance-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations in the Shank proteome (Shank3)), neurodevelopmental disorders (including Rett syndrome and complex tuberous sclerosis), multiple sclerosis, sterol synthesis disorders, pain (including acute and chronic pain), encephalopathy secondary to medical conditions (including hepatic encephalopathy and anti-NMDA receptor encephalitis), seizures (including status epilepticus and monogenic forms of epilepsy such as Dravet disease), stroke, traumatic brain injury, motor disorders (including Huntington's disease and Parkinson's disease), visual impairment, hearing loss, or tinnitus.

[1092] 174. According to the method of 165, the condition described is a sterol synthesis condition.

Claims

1. A compound selected from: , , , and ; Or its pharmaceutically acceptable salt.

2. The compound of claim 1, wherein the compound is selected from: , , , and .

3. The compound of claim 1, wherein the compound is a pharmaceutically acceptable salt selected from the group consisting of: , , , and .

4. A pharmaceutical composition comprising a compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier thereof.

5. Use of any compound of claims 1-3 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inducing sedation or anesthesia.

6. Use of any compound of claims 1-3 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating conditions selected from: gastrointestinal disorders, anal disorders, colonic polyps, cancer, metabolic disorders, and autoimmune diseases.

7. The use of claim 6, wherein the gastrointestinal condition is selected from constipation, irritable bowel syndrome, inflammatory bowel disease, and structural conditions affecting the gastrointestinal tract.

8. The use of claim 6, wherein the anal condition is selected from hemorrhoids, anal fissures, perianal abscesses, and anal fistulas.

9. The use of claim 8, wherein the hemorrhoids are internal or external hemorrhoids.

10. The use of claim 6, wherein the metabolic disorder is diabetes or a sterol synthesis disorder.

11. The use of claim 6, wherein the condition is colitis.

12. The use of claim 11, wherein the colitis is ulcerative colitis.

13. The use of claim 7, wherein the structural condition affecting the gastrointestinal tract is Crohn's disease.

14. Use of any compound of claims 1-3 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a condition selected from: rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis.

15. Use of any compound of claims 1-3 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating CNS-related disorders, wherein the CNS-related disorders are selected from: adjustment disorders, anxiety disorders, eating disorders, mood disorders, schizophrenia or other psychosis, sleep disorders, substance-related disorders, personality disorders, neurodevelopmental disorders, multiple sclerosis, sterol synthesis disorders, pain, encephalopathy secondary to medical conditions, seizures, stroke, traumatic brain injury, movement disorders, visual impairment, hearing loss, and tinnitus.

16. The use of claim 15, wherein the anxiety disorder is a dissociative disorder.

17. Use of any compound of claims 1-3 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cognitive impairment or autism spectrum disorder.

18. The use of claim 17, wherein the cognitive impairment is Alzheimer's disease or other forms of dementia.

19. The use of claim 15, wherein the affective disorder is a dysphoric disorder.

20. The use of claim 15, wherein the encephalopathy secondary to a medical condition is hepatic encephalopathy or anti-NMDA receptor encephalitis.

21. The use of claim 15, wherein the movement disorder is Huntington's disease or Parkinson's disease.

22. Use of any compound of claims 1-3 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention of conditions selected from: gastrointestinal disorders, anal disorders, colonic polyps, cancer, metabolic disorders and autoimmune diseases.

23. The use of claim 22, wherein the gastrointestinal condition is selected from constipation, irritable bowel syndrome, inflammatory bowel disease, and structural conditions affecting the gastrointestinal tract.

24. The use of claim 22, wherein the anal condition is hemorrhoids.

25. The use of claim 24, wherein the hemorrhoids are internal or external hemorrhoids.

26. The use of claim 22, wherein the anal condition is selected from anal fissure, perianal abscess, and anal fistula.

27. The use of claim 22, wherein the metabolic disorder is diabetes or a sterol synthesis disorder.

28. The use of claim 22, wherein the condition is colitis.

29. The use of claim 28, wherein the colitis is ulcerative colitis.

30. The use of claim 23, wherein the structural condition affecting the gastrointestinal tract is Crohn's disease.

31. Use of any compound of claims 1-3 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention of a condition selected from: rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis.

32. Use of any compound of claims 1-3 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention of CNS-related disorders, wherein the CNS-related disorders are selected from: adjustment disorders, anxiety disorders, eating disorders, mood disorders, schizophrenia or other psychosis, sleep disorders, substance-related disorders, personality disorders, neurodevelopmental disorders, multiple sclerosis, sterol synthesis disorders, pain, encephalopathy secondary to medical conditions, seizures, stroke, traumatic brain injury, movement disorders, visual impairment, hearing loss, and tinnitus.

33. The use of claim 32, wherein the anxiety disorder is a dissociative disorder.

34. Use of any compound of claims 1-3 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention of cognitive impairment or autism spectrum disorder.

35. The use of claim 34, wherein the cognitive impairment is Alzheimer's disease or other forms of dementia.

36. The use of claim 32, wherein the emotional disorder is a dysphoric disorder.

37. The use of claim 32, wherein the encephalopathy secondary to a medical condition is hepatic encephalopathy or anti-NMDA receptor encephalitis.

38. The use of claim 32, wherein the movement disorder is Huntington's disease or Parkinson's disease.

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