Oxysterols and methods of use thereof

Abstract

To provide oxysterols and methods of use thereof.SOLUTION: The present invention provides compounds according to a Formula (I) in the figure and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. In the formula, R2, R3, R4, R5 and R6 are as defined herein. Compounds of the present invention are expected to be useful for prevention and treatment of a variety of conditions. NMDA receptors are heteromeric complexes comprising NR1, NR2 and / or NR3 subunits, and possess distinct recognition sites for exogenous and endogenous ligands. These recognition sites include binding sites for glycine, and glutamate agonists and modulators.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related Applications This application claims priority to and the benefit of U.S. Provisional Application No. 62 / 409,761, filed October 18, 2016, U.S. Provisional Application No. 62 / 409,767, filed October 18, 2016, U.S. Provisional Application No. 62 / 409,772, filed October 18, 2016, U.S. Provisional Application No. 62 / 409,774, filed October 18, 2016, and U.S. Provisional Application No. 62 / 409,764, filed October 18, 2016, each of which is incorporated herein by reference in its entirety. [Background technology]

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

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

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

[0005] In one aspect, the compound of formula (I-59): [ka] [In the formula, R 2 and R 3 each is independently hydrogen, alkyl (e.g., C1-C6 alkyl), carbocyclyl, or heterocyclyl, or R 2 and R 3 form a 3- to 8-membered ring together with the carbon atoms to which they are attached; R 4 and R 5 each independently represents hydrogen, halo, or -OR C where R Cis hydrogen or alkyl (e.g., C1-C6 alkyl), or R 4 and R 5 form an oxo group together with the carbon atom to which they are attached; R 6 is absent or is hydrogen; and [ka] represents a single or double bond, where: [ka] If one of the is a double bond, the other [ka] is a single bond; [ka] If both are single bonds, R 6 is hydrogen; and [ka] If one of the groups is a double bond, R 6 does not exist] or a pharmaceutically acceptable salt thereof [provided that the following compounds: [ka] are excluded] are provided herein.

[0006] In some embodiments, R 2 is hydrogen or alkyl (e.g., C1-C6 alkyl). In some embodiments, R 2 is haloalkyl (eg, C1-C6 haloalkyl).

[0007] In some embodiments, R 2 and R 3 Each of R is independently alkyl (e.g., substituted C1-C6 alkyl) or hydrogen.2 and R 3 each independently represents an unsubstituted alkyl (e.g., an unsubstituted C1-C6 alkyl) or water In some embodiments, R 2 and R 3 Each of R is independently C1-C6 haloalkyl (e.g., trifluoromethyl) or hydrogen. 2 and R 3 Each of R is independently hydrogen, carbocyclyl, or heterocyclyl. 2 and R 3 Each of R is independently C2-C6 alkyl (e.g., isopropyl or tert-butyl) or hydrogen. 2 and R 3 Each of is independently hydrogen or C3-C6 alkyl (e.g., isopropyl or tert-butyl).

[0008] In some embodiments, R 2 and R 3 at least one of R is C-C alkyl (e.g., isopropyl or tert-butyl), carbocyclyl, or heterocyclyl; or R 2 and R 3 together with the carbon atoms to which they are attached form a 3- to 8-membered ring. In some embodiments, R 2 is isopropyl or tert-butyl, and R 3 is methyl or hydrogen. In some embodiments, R 2 is a substituted isopropyl or substituted tert-butyl, and R 3 is unsubstituted methyl or hydrogen. In some embodiments, R 2 is unsubstituted isopropyl or unsubstituted tert-butyl, and R 3 is unsubstituted methyl or hydrogen. In some embodiments, R 2 is tert-butyl, and R 3 is hydrogen. In some embodiments, R2 is a substituted tert-butyl, and R 3 is hydrogen. In some embodiments, R 2 is unsubstituted tert-butyl, and R 3 is hydrogen. In some embodiments, R 2 is trifluoromethyl, and R 3 is hydrogen. In some embodiments, R 2 is trifluoromethyl, and R 3 is methyl. In some embodiments, R 2 is trifluoromethyl, and R 3 is substituted methyl. In some embodiments, R 2 is trifluoromethyl, and R 3 is unsubstituted methyl. In some embodiments, R 2 is methyl, and R 3 is hydrogen. In some embodiments, R 2 is a substituted methyl, and R 3 is hydrogen. In some embodiments, R 2 is unsubstituted methyl, and R 3 is hydrogen.

[0009] In some embodiments, the 3- to 8-membered ring is heterogeneous or homogeneous. In some further embodiments, the heterogeneous or homogeneous 3- to 8-membered ring is substituted with alkyl, haloalkyl, 3- to 6-membered ring, substituted or unsubstituted alkoxy, or OH.

[0010] In some embodiments, R 4 is —OH or halo (e.g., —F). In some embodiments, R 4 and R 5 together with the carbon atom to which they are attached form an oxo group. In some embodiments, R 4 is hydrogen, and R 5 is halo (e.g., -F). In some embodiments, R4 and R 5 is halo (e.g., -F). In some embodiments, R 4 and R 5 is hydrogen.

[0011] In some embodiments, R 2 and R 3 together with the carbon atoms to which they are attached form a five-membered ring. 2 is C2-C6 alkyl (e.g., substituted or unsubstituted isopropyl or substituted or unsubstituted tert-butyl), and R 3 is C1-C6 alkyl (e.g., substituted or unsubstituted C1-C6 alkyl). In some embodiments, R 2 is unsubstituted C2-C6 alkyl (e.g., unsubstituted isopropyl or unsubstituted tert-butyl), and R 3 is unsubstituted C1-C6 alkyl. In some embodiments, R 2 and R 3 form a six-membered ring together with the carbon atoms to which they are attached.

[0012] In some embodiments, R 2 is carbocyclyl or heterocyclyl, and R 3 is hydrogen. In some embodiments, R 2 and R 3 is hydrogen. In some embodiments, R 2 is isopropyl, and R 3 is hydrogen. In some embodiments, R 2 is substituted isopropyl, and R 3 is hydrogen. In some embodiments, R 2 is substituted isopropyl, and R 3 is hydrogen. In some embodiments, R 2 and R 3together with the carbon atoms to which they are attached form a 3- to 8-membered carbocyclic ring (e.g., cyclohexyl) or heterocyclic ring (e.g., tetrahydrofuranyl or tetrahydropyranyl). In some embodiments, the carbocyclic or heterocyclic ring is substituted (e.g., a ring substituted with one or two halo or alkyl groups). In some embodiments, R 2 is cyclobutyl, and R 3 is hydrogen. In some embodiments, R 2 is tetrahydropyranyl, and R 3 is hydrogen.

[0013] In some embodiments, R 2 is a substituted cyclobutyl, and R 3 is hydrogen. In some embodiments, R 2 is a substituted tetrahydropyranyl, and R 3 is hydrogen. In some embodiments, R 2 is unsubstituted cyclobutyl, and R 3 is hydrogen. In some embodiments, R 2 is unsubstituted tetrahydropyranyl, and R 3 is hydrogen.

[0014] In some embodiments, the compound of formula (I-59) has formula (I-A59), (I-B59), or (I-C59): [ka] The compound is selected from the group consisting of:

[0015] In some embodiments, the compound of formula (I-59) has the formula (I-B59): [ka] The compound is selected from the group consisting of:

[0016] In some embodiments, the compound of formula (I-59) has the formula (I-C59): [ka] The compound is selected from the group consisting of:

[0017] In some embodiments, R 2 and R 3 at least one of R is hydrogen, C1-C6 alkyl, carbocyclyl, or heterocyclyl; or R 2 and R 3 together with the carbon atoms to which they are attached form a 3-8 membered ring. In some embodiments, the compound of formula (I-59) has the formula (I-D59): [ka] The compound is selected from the group consisting of:

[0018] In some embodiments, the compound of formula (I-59) has the formula (I-E59): [ka] The compound is selected from the group consisting of:

[0019] In some embodiments, the compound of formula (I-59) has the formula (ID-i59) or (ID-ii59): [ka] The compound is selected from the group consisting of:

[0020] In some embodiments, the compound of formula (I-59) has the formula (IE-i59) or (IE-ii59): [ka] The compound is selected from the group consisting of:

[0021] In some embodiments, the compound is [ka] [ka] is.

[0022] In one aspect, the compound of formula (I-66): [ka] [In the formula, R 1 is alkyl (e.g., C1-C6 alkyl); R 2 is aralkyl, heteroaralkyl, aryl, or heteroaryl; R 3 is hydrogen, alkyl (e.g., C1-C6 alkyl), carbocyclyl, heterocyclyl, aryl, or heteroaryl; R 4 and R 5 each independently represents hydrogen, halo, or -OR C where R C is hydrogen or C1-C3 alkyl (e.g., unsubstituted or substituted C1-C3 alkyl), or R 4 and R 5 form an oxo group together with the carbon atom to which they are attached; R 6 is absent or is hydrogen; and [ka] represents a single or double bond, where: [ka] If one of the is a double bond, the other [ka] is a single bond; [ka] If both are single bonds, R 6 is hydrogen; and [ka] If one of the groups is a double bond, R 6 is not present], or a pharmaceutically acceptable salt thereof.

[0023] In some embodiments, R 1 is alkyl (e.g., C1-C6 alkyl). In some embodiments, R 1 is C1-C6 alkyl (e.g., -CH3, -CH2CH3, -CH2OCH3, or -CF3). In some embodiments, R 1 is -CH, -CF, or -CHCH. In some embodiments, R 1 Ha-CH2OR A where R A is C1 to C6 alkyl (for example, C1 to C3 alkyl).

[0024] It should be recognized that the C1-C6 alkyl, aralkyl, heteroaralkyl, aryl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or heteroaryl may be substituted or unsubstituted, for example, with cyano, halogen, OH, or alkoxy.

[0025] In some embodiments, R 2 is aryl (e.g., substituted or unsubstituted aryl, e.g., substituted or unsubstituted phenyl), heteroaryl (e.g., substituted or unsubstituted heteroaryl, e.g., substituted or unsubstituted pyridyl), or aralkyl (e.g., substituted or unsubstituted benzyl). In some embodiments, R 2 is phenyl (eg, substituted or unsubstituted phenyl), pyridyl (eg, substituted or unsubstituted pyridyl), or benzyl (eg, substituted or unsubstituted benzyl).

[0026] In some embodiments, R 3 is hydrogen or alkyl (e.g., C1-C6 alkyl). In some embodiments, R 3is hydrogen, unsubstituted alkyl (eg, unsubstituted C1-C6 alkyl), or haloalkyl (eg, -CF3).

[0027] In some embodiments, R 4 is —OH or halo (e.g., —F).

[0028] In some embodiments, R 4 and R 5 together with the carbon atom to which they are attached form an oxo group. In some embodiments, R 4 is hydrogen, and R 5 is halo (e.g., -F). In some embodiments, R 4 and R 5 is halo (e.g., -F). In some embodiments, R 4 and R 5 is hydrogen.

[0029] In some embodiments, R 2 is aryl (e.g., substituted or unsubstituted aryl, e.g., substituted or unsubstituted phenyl), heteroaryl (e.g., substituted or unsubstituted heteroaryl, e.g., substituted or unsubstituted pyridyl), aralkyl (e.g., substituted or unsubstituted aralkyl, e.g., substituted or unsubstituted benzyl) or heteroaralkyl, and R 3 is hydrogen or alkyl (e.g., unsubstituted C1-C6 alkyl, e.g., C1-C6 haloalkyl). In some embodiments, R 2 is aryl (e.g., substituted or unsubstituted aryl, e.g., substituted or unsubstituted phenyl), heteroaryl (e.g., substituted or unsubstituted heteroaryl, e.g., substituted or unsubstituted pyridyl), aralkyl (e.g., substituted or unsubstituted aralkyl, e.g., substituted or unsubstituted benzyl) or heteroaralkyl, and R 3 is hydrogen, -CH3 or -CF3 .

[0030] In some embodiments, R 1is alkyl (e.g., C1-C6 alkyl), and R 2 is aryl (e.g., substituted or unsubstituted aryl, e.g., substituted or unsubstituted phenyl), heteroaryl (e.g., substituted or unsubstituted heteroaryl, e.g., substituted or unsubstituted pyridyl), aralkyl (e.g., substituted or unsubstituted aralkyl, e.g., substituted or unsubstituted benzyl) or heteroaralkyl, and R 3 is hydrogen, —CH or —CF. In some embodiments, R 1 is -CH3 or -CH2CH3, and R 2 is unsubstituted phenyl, unsubstituted pyridyl, or unsubstituted benzyl, and R 3 is hydrogen, -CH3 or -CF3.

[0031] In some embodiments, the compound of formula (I-66) has formula (I-A66), (I-B66), or (I-C66): [ka] The compound is selected from the group consisting of:

[0032] In some embodiments, the compound of formula (I-66) has the formula (I-A66): [ka] The compound is selected from the group consisting of:

[0033] In some embodiments, the compound is [ka] [ka] is.

[0034] In one aspect, the compound of formula (I-61): [ka] [In the formula, R 1is hydrogen or alkyl (e.g., C1-C6 alkyl); R 2 and R 3 each is independently hydrogen, alkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, or R 2 and R 3 form a 3- to 8-membered ring together with the carbon atoms to which they are attached; R 4 and R 5 each independently represents hydrogen, halo, or -OR C where R C is hydrogen or alkyl (e.g., C1-C6 alkyl), or R 4 and R 5 form an oxo group together with the carbon atom to which they are attached; R 6 is absent or is hydrogen; and [ka] represents a single or double bond, where: [ka] If one of the is a double bond, the other [ka] is a single bond; [ka] If both are single bonds, R 6 is hydrogen; and [ka] If one of the groups is a double bond, R 6 does not exist] or a pharmaceutically acceptable salt thereof [provided that the following compounds: [ka] [ka] are excluded] are provided herein.

[0035] In some embodiments, R 1 is alkyl (e.g., C1-C6 alkyl) or hydrogen. In some embodiments, R 1 is C2-C6 alkyl (e.g., C3-C6 alkyl) or hydrogen. In some embodiments, R 1 is a substituted or unsubstituted C2-C6 alkyl (e.g., a substituted or unsubstituted C3-C6 alkyl) or hydrogen In some embodiments, R 1 is methyl or ethyl (e.g., substituted or unsubstituted methyl or substituted or unsubstituted ethyl). In some embodiments, R 1 is substituted or unsubstituted methyl or substituted or unsubstituted ethyl. In some embodiments, R 1 is trifluoromethyl. In some embodiments, R 1 Ha-CH2OR A where R A is C1 to C6 alkyl (for example, C1 to C3 alkyl).

[0036] In some embodiments, R 2 is hydrogen or C1-C6 alkyl (e.g., C2-C6 alkyl). In some embodiments, R 2 is hydrogen or substituted or unsubstituted C1-C6 alkyl (e.g., substituted or unsubstituted C2-C6 alkyl). In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is isopropyl (e.g., substituted or unsubstituted isopropyl). In some embodiments, R 2 is substituted or unsubstituted isopropyl. In some embodiments, R 2 is haloalkyl (eg, C1-C6 haloalkyl).

[0037] In some embodiments, R 2 and R3 Each of R is independently alkyl (e.g., C1-C6 alkyl) or hydrogen. 2 and R 3 Each of R is independently substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl) or hydrogen. 2 and R 3 together with the carbon atoms to which they are attached form a 3- to 8-membered ring. In some embodiments, R 2 and R 3 Each of is independently hydrogen or C1-C6 alkyl (e.g., C2-C6 alkyl). In some embodiments, R 2 and R 3 is independently hydrogen or substituted or unsubstituted C1-C6 alkyl (e.g., substituted or unsubstituted C2-C6 alkyl). 2 and R 3 Each of R is independently hydrogen or C-C alkyl (e.g., isopropyl). 2 and R 3 Each of is independently hydrogen or substituted or unsubstituted C3-C6 alkyl (eg, substituted or unsubstituted isopropyl).

[0038] In some embodiments, R 4 is —OH or halo (e.g., —F). In some embodiments, R 4 and R 5 together with the carbon atom to which they are attached form an oxo group. In some embodiments, R 4 is hydrogen, and R 5 is halo (e.g., -F). In some embodiments, R 4 and R 5 is halo (e.g., -F). In some embodiments, R 4 and R 5 is hydrogen.

[0039] In some embodiments, R2 and R 3 is hydrogen. In some embodiments, R 2 is C1-C6 alkyl, and R 3 is C2-C6 alkyl (e.g., C3-C6 alkyl). In some embodiments, R 2 is a substituted or unsubstituted C1-C6 alkyl, and R 3 is a substituted or unsubstituted C2-C6 alkyl (e.g., a substituted or unsubstituted C3-C6 alkyl). In some embodiments, R 1 is ethyl (e.g., substituted or unsubstituted ethyl), and R 2 and R 3 is methyl (e.g., substituted or unsubstituted methyl). In some embodiments, R 1 is substituted or unsubstituted ethyl, and R 2 and R 3 is substituted or unsubstituted methyl. In some embodiments, R 1 is ethyl, and R 2 is isopropyl, and R 3 is hydrogen. In some embodiments, R 1 is a substituted or unsubstituted ethyl, and R 2 is substituted or unsubstituted isopropyl, and R 3 is hydrogen. In some embodiments, R 1 is ethyl, and R 2 is isopropyl, and R 3 is methyl. In some embodiments, R 1 is a substituted or unsubstituted ethyl, and R 2 is substituted or unsubstituted isopropyl, and R 3 is substituted or unsubstituted methyl.

[0040] In some embodiments, the compound of formula (I-61) has formula (I-A61), (I-B61), or (I-C61): [ka] is a compound of

[0041] In some embodiments, the compound of formula (I-61) has the formula (I-C61): [ka] The compound is selected from the group consisting of:

[0042] In some embodiments, the compound of formula (I-61) has the formula (I-A61): [ka] The compound is selected from the group consisting of:

[0043] In some embodiments, the compound of formula (I-61) has the formula (IC-i61) or (IC-ii61): [ka] The compound is selected from the group consisting of:

[0044] In some embodiments, the compound is [ka] [ka] is.

[0045] In one aspect, the present invention provides a compound of formula (I-62): [ka] [In the formula, R 1 is hydrogen or alkyl (e.g., C1-C6 alkyl); R 2 and R 3 each is independently hydrogen, alkyl, carbocyclyl, or heterocyclyl, or R 2 and R 3 form a 3- to 8-membered ring together with the carbon atoms to which they are attached; R 4and R 5 each independently represents hydrogen, halo, or -OR C where R C is hydrogen or alkyl (e.g., C1-C6 alkyl), or R 4 and R 5 form an oxo group together with the carbon atom to which they are attached; R 6 is absent or is hydrogen; and [ka] represents a single or double bond, where: [ka] If one of the is a double bond, the other [ka] is a single bond; [ka] If both are single bonds, R 6 is hydrogen; and [ka] If one of the groups is a double bond, R 6 is absent] or a pharmaceutically acceptable salt thereof.

[0046] In some embodiments, R 1 is alkyl (e.g., C1-C6 alkyl). In some embodiments, R 1 is a substituted or unsubstituted C2-C6 alkyl (e.g., a substituted or unsubstituted C3-C6 alkyl). In some embodiments, R 1 is methyl or ethyl (e.g., substituted or unsubstituted methyl or substituted or unsubstituted ethyl). In some embodiments, R 1is substituted or unsubstituted methyl or substituted or unsubstituted ethyl. In some embodiments, R 1 is trifluoromethyl. In some embodiments, R 1 Ha-CH2OR A where R A is C1 to C6 alkyl (for example, C1 to C3 alkyl).

[0047] In some embodiments, R 2 is hydrogen or C1-C6 alkyl (e.g., C2-C6 alkyl). In some embodiments, R 2 is hydrogen or substituted or unsubstituted C1-C6 alkyl (e.g., substituted or unsubstituted C2-C6 alkyl). In some embodiments, R 2 is haloalkyl (eg, C1-C6 haloalkyl).

[0048] In some embodiments, R 2 and R 3 Each of is independently hydrogen or C1-C6 alkyl (e.g., C2-C6 alkyl). In some embodiments, R 2 and R 3 is independently hydrogen or substituted or unsubstituted C1-C6 alkyl (e.g., substituted or unsubstituted C2-C6 alkyl). 2 and R 3 Each of R is independently alkyl (e.g., C1-C6 alkyl) or hydrogen. 2 and R 3 Each of R is independently substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl) or hydrogen. 2 and R 3 form a 3- to 8-membered ring together with the carbon atoms to which they are attached.

[0049] In some embodiments, R 4is —OH or halo (e.g., —F). In some embodiments, R 4 and R 5 together with the carbon atom to which they are attached form an oxo group. In some embodiments, R 4 is hydrogen, and R 5 is halo (e.g., -F). In some embodiments, R 4 and R 5 is halo (e.g., -F). In some embodiments, R 4 and R 5 is hydrogen.

[0050] In some embodiments, R 1 is ethyl (e.g., substituted or unsubstituted ethyl), and R 2 and R 3 is methyl (e.g., substituted or unsubstituted methyl). In some embodiments, R 1 is substituted or unsubstituted ethyl, and R 2 and R 3 is substituted or unsubstituted methyl.

[0051] In some embodiments, the compound of formula (I-62) has formula (I-A62), (I-B62), or (I-C62): [ka] is a compound of

[0052] In some embodiments, the compound of formula (I-62) has the formula (I-C62): [ka] The compound is selected from the group consisting of:

[0053] In some embodiments, the compound of formula (I-62) has the formula (I-A62): [ka] The compound is selected from the group consisting of:

[0054] In some embodiments, R 1 is ethyl (e.g., substituted or unsubstituted ethyl), and R 2 and R 3 is methyl (e.g., substituted or unsubstituted methyl). In some embodiments, R 1 is substituted or unsubstituted ethyl, and R 2 and R 3 is substituted or unsubstituted methyl.

[0055] In some embodiments, the compound of formula (I-62) has the formula (IC-i62) or (IC-ii62): [ka] The compound is selected from the group consisting of:

[0056] In some embodiments, the compound is [ka] is.

[0057] In one aspect, the compound of formula (I-60): [ka] [In the formula, R 2 and R 3 each is independently hydrogen, alkyl (e.g., C1-C6 alkyl), carbocyclyl, heterocyclyl, aryl, or heteroaryl, or R 2 and R 3 form a 3- to 8-membered ring together with the carbon atoms to which they are attached; R 4 and R 5 each independently represents hydrogen, halo, or -OR C where R C is hydrogen or alkyl (e.g., C1-C6 alkyl), or R 4 and R5 form an oxo group together with the carbon atom to which they are attached; R 6 is absent or is hydrogen; and [ka] represents a single or double bond, where: [ka] If one of the is a double bond, the other [ka] is a single bond; [ka] If both are single bonds, R 6 is hydrogen; and [ka] If one of the groups is a double bond, R 6 is not present], or a pharmaceutically acceptable salt thereof. In some embodiments, R 2 is alkyl (e.g., C1-C6 alkyl) or hydrogen. In some embodiments, R 2 is haloalkyl (e.g., C1-C6 haloalkyl). In some embodiments, R 2 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl) or hydrogen. In some embodiments, R 2 is aryl or heteroaryl. In some embodiments, R 2 and R 3 Each of R is independently alkyl (e.g., C1-C6 alkyl) or hydrogen. 2 and R 3Each of R is independently substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl) or hydrogen. 2 and R 3 Each of R is independently unsubstituted alkyl (e.g., unsubstituted C1-C6 alkyl) or hydrogen. 2 and R 3 Each of R is independently C1-C6 haloalkyl (e.g., trifluoromethyl) or hydrogen. 2 and R 3 Each of R is independently aryl or heteroaryl. 2 and R 3 form a three-membered ring together with the carbon atoms to which they are attached. In some embodiments, R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropane. In some embodiments, R 2 and R 3 together with the carbon atoms to which they are attached form a 3- to 8-membered carbocyclic or heterocyclic ring. In some embodiments, R 2 is carbocyclyl or heterocyclyl, and R 3 is hydrogen. In some embodiments, R 2 is trifluoromethyl, and R 3 is hydrogen. In some embodiments, R 2 is aryl or heteroaryl, and R 3 is hydrogen. In some embodiments, R 2 and R 3 is methyl (e.g., substituted or unsubstituted methyl). In some embodiments, R 2 and R 3 is substituted methyl. In some embodiments, R 2 and R 3 is unsubstituted methyl. In some embodiments, R 4is —OH or halo (e.g., —F). In some embodiments, R 4 and R 5 together with the carbon atom to which they are attached form an oxo group. In some embodiments, R 4 is hydrogen, and R 5 is halo (e.g., -F). In some embodiments, R 4 and R 5 is halo (e.g., -F). In some embodiments, R 4 and R 5 is hydrogen. In some embodiments, the compound of formula (I-60) has formula (I-A60), (I-B60), or (I-C60): [ka] The compound is selected from the group consisting of: In some embodiments, the compound of formula (I-60) has the formula (I-B60): [ka] The compound is selected from the group consisting of: In some embodiments, R 2 and R 3 at least one of is C1-C6 alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R 2 and R 3 form a 3- to 8-membered ring together with the carbon atoms to which they are attached. In some embodiments, R 2 is methyl, and R 3 is hydrogen. In some embodiments, R 2 is unsubstituted methyl, and R 3 is hydrogen. In some embodiments, R 2 and R 3 is hydrogen. In some embodiments, the compound is [ka] is.

[0058] In one aspect, provided herein is a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0059] In certain aspects, provided herein are methods of inducing sedation or anesthesia, the methods comprising administering to a subject an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0060] In one aspect, provided herein is a method for treating or preventing a disorder described herein, the method comprising administering to a subject in need thereof an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0061] In some embodiments, the disorder is a metabolic disorder.

[0062] In some embodiments, the disorder is an autoimmune disorder.

[0063] In some embodiments, the disorder is rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and plaque psoriasis.

[0064] In some embodiments, the disorder is a gastrointestinal (GI) disorder, such as constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) (e.g., ulcerative colitis, Crohn's disease), structural disorders affecting the GI, anal disorders (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas), colon polyps, cancer, or colitis.

[0065] In some embodiments, the disorder is inflammatory bowel disease.

[0066] In some embodiments, the disorder is cancer, diabetes, or a sterol synthesis disorder.

[0067] In some embodiments, the disorder is neuropsychiatric lupus ), depression, OCD, Huntington's disease, ALS, Alzheimer's disease, dementia, Parkinson's disease, MS, acute liver failure, glycine encephalopathy, tinnitus, neuropathic pain, migraine, genetic epilepsy, seizures, ataxia, levodopa-induced dyskinesia, fragile X, Rett syndrome, autism spectrum disorder, Tourette's, schizophrenia, and traumatic brain injury.

[0068] In one aspect, provided herein is a method for treating or preventing a CNS-related condition, comprising administering to a subject in need thereof an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the CNS-related condition is an adjustment disorder, an anxiety disorder (including obsessive-compulsive disorder, post-traumatic stress disorder, and social phobia), a cognitive disorder (including Alzheimer's disease and other forms of dementia (e.g., frontotemporal dementia)), a dissociative disorder, an eating disorder, a mood disorder (including depression (e.g., postpartum depression)), a bipolar disorder, a dysthymic disorder, a suicidality), a schizophrenia or other psychotic disorder (including schizoaffective psychosis), a sleep disorder (including insomnia), a substance-related disorder, a personality disorder (including obsessive-compulsive personality disorder), an autism spectrum disorder (including Shank's group of protein disorders), or a psychiatric disorder (including psychiatric disorders). These conditions include those involving mutations in proteins (e.g., Shank3), neurodevelopmental disorders (including Rett syndrome, tuberous sclerosis), multiple sclerosis, disorders of sterol synthesis, pain (including acute and chronic pain; headache, e.g., migraine), brain disorders secondary to a medical condition (including hepatic encephalopathy and anti-NMDA receptor encephalitis), seizure disorders (including status epilepticus and monogenic forms of epilepsy, e.g., Dravet's disease), stroke, traumatic brain injury, movement disorders (including Huntington's disease and Parkinson's disease), vision impairment, hearing loss, or tinnitus.

[0069] In some embodiments, the disorder is Huntington's disease. In some embodiments, the disorder is Parkinson's disease. In some embodiments, the disorder is an inflammatory disease (e.g., lupus).

[0070] In some embodiments, the disorder is a sterol synthesis disorder.

[0071] In some embodiments, the disorder is Smith-Lemli-Opitz syndrome (SLOS). In some embodiments, the disorder is desmosterolosis. ). In some embodiments, the disorder is sitosterolemia. In some embodiments, the disorder is cerebrotendinous xanthomatosis (CTX). In some embodiments, the disorder is mevalonate kinase deficiency (MKD). In some embodiments, the disorder is an SC4MOL gene mutation (SMO deficiency). In some embodiments, the disorder is Niemann-Pick disease. In some embodiments, the disorder is an autism spectrum disorder (ASD). In some embodiments, the disorder is associated with phenylketonuria.

[0072] Other objects and advantages will become apparent to those skilled in the art from a consideration of the following detailed description, examples, and claims. definition chemical definition

[0073] Definitions of specific functional groups and chemical terms are explained in detail below. Chemical elements are The functional groups are generally defined according to the table (CAS version, Handbook of Chemistry and Physics, 75th edition, inside cover), and specific functional groups are generally defined as described therein.In addition, the general rules of organic chemistry and specific functional moieties and reactivity are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0074] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures, and mixtures enriched in one or more stereoisomers. Isomers may be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and chiral salt formation and crystallization; or preferred isomers may be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates, and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and See Optical Resolutions p. 268 (E.L. Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention further includes the compounds described herein as individual isomers substantially free of other isomers, and alternatively as mixtures of various isomers.

[0075] "Enantiomeric excess" ("ee") or "% enantiomeric excess" ("%ee") of a composition, as used herein, refers to the excess of one enantiomer relative to the other enantiomer present in the composition. For example, a composition may contain 90% of one enantiomer, e.g., the S enantiomer, and 10% of the other enantiomer, i.e., the R enantiomer.

[0076] ee=(90-10) / 100=80%.

[0077] Thus, a composition containing 90% of one enantiomer and 10% of the other is said to have an enantiomeric excess of 80%.

[0078] "Diastereomeric excess" ("de") or "% diastereomeric excess" ("% de") of a composition, as used herein, refers to the 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.

[0079] de=(90-10) / 100=80%.

[0080] Thus, a composition containing 90% of one diastereomer and 10% of one or more different diastereomers is said to have a diastereomeric excess of 80%.

[0081] In alternative embodiments, the compounds 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, a specific isotope (e.g., 3 H, 13 C. 14 C. 18 O or 15N) 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 particular site on the compound.

[0082] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1~6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 , and C 5~6 is intended to encompass alkyl of the formula:

[0083] The following terms are intended to have the meanings provided below and are useful in understanding the specification and the intended scope of the invention. When describing the present invention, which may include compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms, when present, have the following meanings, unless otherwise indicated. As described herein, it should also be understood that any of the moieties defined below can be substituted with various substituents, and that each definition is intended to encompass substituted moieties within their scope as described below. Unless otherwise stated, the term "substituted" is defined as described below. It should further be understood that the terms "group" and "radical" can be considered interchangeable when used herein. The articles "a" and "an" can be used herein to refer to one or more (i.e., at least one) of the grammatical object of the article. By way of example, "an analogue" means one analogue or more than one analogue.

[0084] "Aliphatic" refers to an alkyl, alkenyl, alkynyl, or cycloalkyl group, as defined herein.

[0085] "Cycloalkylalkyl" refers to an alkyl radical in which the alkyl group is substituted with a cycloalkyl group. Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl.

[0086] "Heterocyclylalkyl" refers to an alkyl radical in which the alkyl group is substituted with a heterocyclyl group. Exemplary heterocyclylalkyl groups include pyrrolidinylmethyl, These include, but are not limited to, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl and the like.

[0087] "Aralkyl" is a subset of alkyl and aryl, as defined herein, and refers to an optionally substituted alkyl group substituted with an optionally substituted aryl group.

[0088] "Alkyl" means the radical of a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1~20 In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C 1~12 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1~10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1~9 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1~8 In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1~7 In some embodiments, an alkyl group has 1 to 6 carbon atoms (also referred to herein as "lower alkyl" or "C 1~6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1~5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1~4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1~3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1~2In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2~6 alkyl). C 1~6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each occurrence of an alkyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents; for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1~10 In certain embodiments, the alkyl group is a substituted C 1~10 Common abbreviations for alkyl include Me(-CH), Et(-CHCH), iPr(-CH(CH)), nPr(-CHCHCH), n-Bu(-CHCHCHCHCH), or i-Bu(-CHCH(CH)).

[0089] "Alkylene" refers to an alkyl group in which two hydrogens are removed to provide a divalent radical, and which may be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), butylene (-CHCHCHCHCH-), pentylene (-CHCHCHCHCHCH-), and hexylene (-CHCHCHCHCHCHCH-). Exemplary substituted alkylene groups (e.g., substituted with one or more alkyl (methyl) groups) include substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), and substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(C Examples of alkylene groups include, but are not limited to, -C(CH)CHCH-, -CHCHCH(CH)-, -C(CH)CHCH-, -CHC(CH)CH-, -CHCHC(CH)-), and the like. When a range or number of carbons is provided for a particular alkylene group, it is understood that the range or number refers to the range or number of carbons in a linear divalent chain of carbons. An alkylene group can be substituted or unsubstituted with one or more substituents as described herein.

[0090] "Alkenyl" refers to the radical of a straight- or branched-chain hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and, optionally, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) ("C 2~20 In certain embodiments, an alkenyl group does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C 2~10 In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C2~9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, an alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., 2-butenyl) or terminal (e.g., 1-butenyl). C 2~4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each occurrence of an alkenyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2~10 In certain embodiments, the alkenyl group is a substituted C 2~10 It is alkenyl.

[0091] "Alkynyl" refers to the radical of a straight- or branched-chain hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and, optionally, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) ("C 2~20 In certain embodiments, alkynyl groups contain no double bonds. In some embodiments, alkynyl groups have 2 to 10 carbon atoms ("C 2~10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2~5 alkynyl"). In some embodiments. In the formula, the alkynyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (e.g., 2-butynyl) or terminal (e.g., 1-butynyl). C 2~4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4Alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Further examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each occurrence of an alkynyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents; for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2~10 In certain embodiments, the alkynyl group is a substituted C 2~10 It is alkynyl.

[0092] The term "heteroalkyl," as used herein, refers to an alkyl group, as defined herein, that further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) in its parent chain, wherein the one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or the one or more heteroatoms are inserted between a carbon atom and its parent molecule (i.e., between the points of attachment). In certain embodiments, a heteroalkyl group refers to a saturated group having 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~10 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~9 In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~8 In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~7In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ("heteroC 1~6 In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("heteroC 1~5 In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms ("heteroC 1~4 In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom ("heteroC 1~3 In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom ("heteroC 1~2 In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroC alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 2-6 carbon atoms and 1 or 2 heteroatoms ("heteroC 2~6 Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted (a "substituted heteroalkyl") with one or more substituents. In certain embodiments, a heteroalkyl group is an unsubstituted heteroC 1~10 In certain embodiments, the heteroalkyl group is a substituted heteroC 1~10 It is alkyl.

[0093] "Aryl" means an aromatic ring system containing 6 to 14 ring carbon atoms and 0 heteroatoms. The radicals of the provided monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring systems (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) ("C 6~14In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14 "Aryl"; e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, where the bonding radical or point of attachment is on the aryl ring, and in such cases the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene.Specifically, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.Unless otherwise specified, each occurrence of the aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, the aryl group is an unsubstituted C 6~14 In certain embodiments, the aryl group is a substituted C 6~14 It is aryl.

[0094] In certain embodiments, the aryl group is substituted with one or more groups selected from halo, C1-C8 alkyl, C1-C8 haloalkyl, cyano, hydroxy, C1-C8 alkoxy, and amino.

[0095] Representative examples of substituted aryl include: [ka] where R 56 and R 57 can be hydrogen, and R 56 and R 57 At least one of the following is independently selected from C1-C8 alkyl, C1-C8 haloalkyl, 4- to 10-membered heterocyclyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 , N.R. 58 SOR 59 , N.R. 58 SO2R 59 , COO alkyl, COO aryl, CONR 58 R 59 ,CONR 58 OR 59 , N.R. 58 R 59 , SO2NR 58 R 59 , S-alkyl, SO alkyl, SO alkyl, S aryl, SO aryl, SO aryl; or R 56 and R 57 may be linked to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms (optionally containing one or more heteroatoms selected from the group N, O, or S). 60 and R 61 are independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, substituted C6-C 10 It is aryl, 5- to 10-membered heteroaryl or substituted 5- to 10-membered heteroaryl.

[0096] A "fused aryl" is an aryl ring in which two of its ring carbons are common to a second aryl or heteroaryl ring, or to a carbocyclyl or heterocyclyl ring. This refers to the

[0097] "Heteroaryl" refers to a radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π-electrons shared in a cyclic arrangement) in which ring carbon atoms and 1 to 4 ring heteroatoms are provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, if valence allows. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, where the point of attachment is on the heteroaryl ring; in such cases, the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, wherein the point of attachment can be on either the aryl ring or the heteroaryl ring; in such cases, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on the ring with a heteroatom (e.g., 2-indolyl) or on the ring without a heteroatom (e.g., 5-indolyl).

[0098] In some embodiments, heteroaryl groups are 5- to 10-membered aromatic ring systems having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, heteroaryl groups are 5- to 8-membered aromatic ring systems having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In some embodiments, heteroaryl groups are 5- to 6-membered aromatic ring systems having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heteroaryl"). In some embodiments, 5- to 6-membered heteroaryls have 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each occurrence of a heteroaryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, a heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, a heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0099] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0033] Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0100] Representative examples of heteroaryls include: [ka] wherein each Z is a carbonyl, N, NR 65 , O and S; R 65 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5- to 10-membered heteroaryl.

[0101] "Carbocyclyl" or "carbocyclic" means a ring system having 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10 carbocyclyl). Exemplary C 3~6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. 3~8 The carbocyclyl group includes the above-mentioned C 3~6 Examples include, but are not limited to, carbocyclyl groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. 3~10 The carbocyclyl group includes the above-mentioned C 3~8Carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), de Carbohydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ) and the like. As the foregoing examples are illustrated, in certain embodiments, a carbocyclyl group is monocyclic ("monocyclic carbocyclyl") or contains a fused, bridged, or spiro ring system (e.g., a bicyclic system ("bicyclic carbocyclyl")), which may be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, where the point of attachment is on the carbocyclyl ring; in such cases, the number of carbons continues to refer to the number of carbons in the carbocyclyl ring system. Unless otherwise specified, each occurrence of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, a carbocyclyl group is an unsubstituted C 3~10 In certain embodiments, the carbocyclyl group is a substituted C 3~10 It is a carbocyclyl.

[0102] In some embodiments, "carbocyclyl" refers to a monocyclic saturated carbocyclyl group having 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5~6In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5~10 Cycloalkyl). C 5~6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3~6 Examples of cycloalkyl groups include the above-mentioned C 5~6 Cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4). 3~8 Examples of cycloalkyl groups include the above-mentioned C 3~6 Cycloalkyl groups include cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each occurrence of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C 3~10 In certain embodiments, the cycloalkyl group is a substituted C 3~10 It is cycloalkyl.

[0103] "Heterocyclyl" or "heterocyclic" refers to the radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon or nitrogen atom, when valence allows. Heterocyclyl groups can be monocyclic ring systems ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems (e.g., bicyclic systems ("bicyclic heterocyclyl")), and can be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups, where the point of attachment is on the carbocyclyl or heterocyclyl ring, or on a ring system in which a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the heterocyclyl ring; in such cases, the number of ring members continues to refer to the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each occurrence of heterocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl. do.

[0104] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heterocyclyl"). In some embodiments, a 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0105] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclic rings) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclic rings) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0106] A "nitrogen-containing heterocyclyl" group refers to a 4- to 7-membered non-aromatic ring group containing at least one nitrogen atom, including, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazines (e.g., N-methylpiperazine). Specific examples include azetidine, piperidone, and the like. Examples include benzoquinone and piperazone.

[0107] "Hetero," when used to describe a compound or a group present on a compound, means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero can apply to any of the hydrocarbyl groups described above having 1 to 5, particularly 1 to 3, heteroatoms (e.g., alkyl, e.g., heteroalkyl; cycloalkyl, e.g., heterocyclyl; aryl, e.g., heteroaryl; cycloalkenyl, e.g., cycloheteroalkenyl, etc.).

[0108] "Acyl" means -C(O)R 20 radical, where R 20 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein. "Alkanoyl" refers to a group in which R 20is an acyl group where the aryl group is a group other than hydrogen. Representative acyl groups include formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), --C(O)-C1-C8 alkyl, and -C(O)-(CH2). t (C6-C 10 aryl), -C(O)-(CH2) t (5-10 membered heteroaryl), -C(O)-(CH2) t (C3-C 10 cycloalkyl) and -C(O)-(CH2) t (4- to 10-membered heterocyclyl) (t is an integer from 0 to 4). 21 is C1-C8 alkyl substituted with halo or hydroxy; or C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl (each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy).

[0109] "Alkoxy" means -OR 29 where R 29 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e., having 1 to 6 carbon atoms. Further particular alkoxy groups have 1 to 4 carbon atoms.

[0110] In certain embodiments, R 29 is amino, substituted amino, C6-C 10 Aryl, aryloxy, carboxyl, cyano, C3-C 10 The "substituted alkoxy" group is a group having one or more substituents selected from the group consisting of cycloalkyl, 4- to 10-membered heterocyclyl, halogen, 5- to 10-membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2-, and aryl-S(O)2-, for example, 1 to 5 substituents, particularly 1 to 3 substituents, and particularly 1 substituent. Exemplary "substituted alkoxy" groups include -O-(CH2) t (C6~C 10 aryl), -O-(CH2) t (5-10 membered heteroaryl), -O-(CH2) t (C3~C 10 cycloalkyl) and -O-(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present may itself be an unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy ... It may be substituted by a substituted C1-C4 haloalkyl, an unsubstituted C1-C4 hydroxyalkyl, or an unsubstituted C1-C4 haloalkoxy or hydroxy. Particularly exemplary "substituted alkoxy" groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2.

[0111] "Amino" refers to the -NH2 radical.

[0112] "Oxo" refers to a -C(=O)- group.

[0113] "Substituted amino" refers to a group of the formula -N(R 38 )2, where R 38is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino protecting group, wherein R 38 At least one of R is not hydrogen. 38 are independently hydrogen, C1-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl or C3-C 10 cycloalkyl; or C1-C8 alkyl substituted with halo or hydroxy; C3-C8 alkenyl substituted with halo or hydroxy; C3-C8 alkynyl substituted with halo or hydroxy, or -(CH2) t (C6~C 10 aryl), -(CH2) t (5-10 membered heteroaryl), -(CH2) t (C3~C 10 cycloalkyl) or -(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 8, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; or both R 38 The groups are linked to form an alkylene group.

[0114] Exemplary "substituted amino" groups include -NR 39 -C1-C8 alkyl, -NR 39 -(CH2) t (C6~C 10 aryl), -NR 39 -(CH2) t (5-10 membered heteroaryl), -NR 39 -(CH2) t (C3~C 10 cycloalkyl) and -NR39 -(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, e.g., 1 or 2, and each R 39 independently represent H or C1-C8 alkyl; any alkyl group present may itself be substituted by halo, substituted or unsubstituted amino, or hydroxy; any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present may itself be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. For the avoidance of doubt, the term "substituted amino" includes alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino groups, as defined below. Substituted amino encompasses both mono- and di-substituted amino groups.

[0115] "Carboxy" refers to the radical --C(O)OH.

[0116] "Cyano" refers to the -CN radical.

[0117] "Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, a halo group is fluoro or chloro.

[0118] "Haloalkyl" refers to an alkyl radical in which the alkyl group is substituted with one or more halogens. Typical haloalkyl groups include, but are not limited to, trifluoromethyl (-CF), difluoromethyl (-CHF), fluoromethyl (-CHF), chloromethyl (-CHCl), dichloromethyl (-CHCl), tribromomethyl (-CHBr), and the like.

[0119] "Hydroxy" refers to the -OH radical.

[0120] "Nitro" refers to the -NO2 radical.

[0121] "Thioketo" refers to the =S group.

[0122] As defined herein, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl groups). In general, the term "substituted," whether preceded by the term "optionally" or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that, when substituted, gives rise to a stable compound, e.g., a compound that does not undergo spontaneous transformation (e.g., by rearrangement, cyclization, elimination, or other reaction). Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents may be the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, any substituents described herein that result in stable compounds. The present invention contemplates any and all such combinations, provided that stable compounds are obtained. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents, as described herein, that satisfy the valence of the heteroatom and thereby form a stable moiety.

[0123] Exemplary carbon atom substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(Rbb )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)SRaa , -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)(N R bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 and 5- to 14-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd or the two geminal hydrogens on the carbon atom are substituted with ═O, ═S, ═NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNRbb S(=O)2R aa , =NR bb or =NOR cc replaced by radicals;

[0124] R aa Each occurrence of, independently, C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R aa groups linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group;

[0125] R bb Each occurrence of is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1~10 Alkyl, C1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R bb groups linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group;

[0126] R cc Each occurrence of is independently hydrogen, C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R cc groups linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group;

[0127] R dd Each occurrence of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee, -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -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, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10aryl, and 5- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group or two geminal R dd the substituents may be linked to form =O or =S;

[0128] R ee Each occurrence of, independently, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group;

[0129] R ff Each occurrence of is independently hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, or two R ff groups linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg substituted with a group;

[0130] R gg Each occurrence of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6Alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C 1~6 Alkyl)3 + X - , -NH(C 1~6 alkyl)2 + X - , -NH2(C 1~6 alkyl) + X - , -NH3 + X - , -N(OC 1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6 alkyl), -NH(OH), -SH, -SC 1~6 Alkyl, -SS(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -CO2H, -CO2(C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -C(=O)NH2, -C(=O)N(C 1~6 alkyl)2, -OC(=O)NH(C 1~6 alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1~6 alkyl), -OC(=NH)(C 1~6 alkyl), -OC(=NH)OC 1~6 Alkyl, -C(=NH)N(C 1~6 alkyl)2, -C(=NH)NH(C 1~6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1~6 alkyl)2, -OC(NH)NH(C 1~6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1~6alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 alkyl), -SO2NH2, -SO2C 1~6 Alkyl, -SO2OC 1~6 Alkyl, -OSO2C 1~6 Alkyl, -SOC 1~6 Alkyl, -Si(C 1~6 alkyl)3, -OSi(C 1~6 alkyl)3-C(=S)N(C 1~6 alkyl)2, C(=S)NH(C 1~6 alkyl), C(=S)NH2, -C(=O)S(C 1~6 alkyl), -C(=S)SC 1~6 Alkyl, -SC(=S)SC 1~6 Alkyl, -P(=O)2(C 1~6 alkyl), -P(=O)(C 1~6 alkyl)2, -OP(=O)(C 1~6 alkyl)2, -OP(=O)(OC 1~6 Alkyl)2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 a Lukenil, C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl; or two geminal R gg The substituents may be linked to form =O or =S; where X - is the counter ion.

[0131] A "counterion" or "anionic counterion" is a negatively charged group associated with a cationic quaternary amino group to maintain electrical neutrality. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. -, H2PO4 - , HSO4 - , SO4 -2 Examples of such ions include sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.) and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0132] Nitrogen atoms may be substituted or unsubstituted, where valence allows, and may include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C6~14 aryl and 5-14 membered heteroaryl, or two R cc The groups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with R aa , R bb , R cc and R dd is as defined above.

[0133] These and other exemplary substituents are described in detail in the detailed description, examples, and claims. It is not intended that the present invention be limited in any way by the exemplary recitation of substituents above. Other definitions

[0134] The term "pharmaceutically acceptable salt" refers to a salt that is suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66, 1-19. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic acids, inorganic bases, organic acids, and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or formed by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, ascorbate, and ascorbate. Paraginate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, Pharmaceutically acceptable salts derived from appropriate bases include lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate salts, etc. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N-methyl-N ... + (C 1~4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed where appropriate using counterions such as halides, hydroxides, carbonates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0135] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, e.g., mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs). In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0136] Disease, disorder, and condition are used interchangeably herein.

[0137] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions taken while a subject is suffering from a particular disease, disorder, or condition to lessen the severity of the disease, disorder, or condition or to delay or slow the progression of the disease, disorder, or condition ("therapeutic treatment"), and also actions taken before a subject begins to suffer from a particular disease, disorder, or condition ("prophylactic treatment").

[0138] Generally, the "effective amount" of a compound refers to an amount sufficient to induce a desired biological response. As will be understood by those skilled in the art, the effective amount of the compound of the present invention may vary depending on factors such as the desired biological goal, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the age, health status, and condition of the subject. The effective amount includes therapeutic treatment and prophylactic treatment.

[0139] As used herein, unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of the disease, disorder, or condition. The term "therapeutically effective amount" refers to an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent. It can include.

[0140] As used herein, unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition, or to prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of the disease, disorder, or condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or an amount that enhances the prophylactic efficacy of another prophylactic agent. DETAILED DESCRIPTION OF THE INVENTION

[0141] Detailed Description of Specific Embodiments of the Invention As generally described above, the present invention provides oxysterols that are useful for preventing and / or treating a wide range of disorders, including, but not limited to, NMDA-mediated disorders. compound

[0142] In one aspect, the compound of formula (I-59): [ka] [In the formula, R 2 and R 3each is independently hydrogen, alkyl (e.g., C1-C6 alkyl), carbocyclyl, or heterocyclyl, or R 2 and R 3 form a 3- to 8-membered ring together with the carbon atoms to which they are attached; R 4 and R 5 each independently represents hydrogen, halo, or -OR C where R C is hydrogen or alkyl (e.g., C1-C6 alkyl), or R 4 and R 5 form an oxo group together with the carbon atom to which they are attached; R 6 is absent or is hydrogen; and [ka] represents a single or double bond, where: [ka] If one of the is a double bond, the other [ka] is a single bond; [ka] If both are single bonds, R 6 is hydrogen; and [ka] If one of the groups is a double bond, R 6 does not exist] or a pharmaceutically acceptable salt thereof [provided that the following compounds: [ka] are excluded] are provided herein.

[0143] In some embodiments, R 2is hydrogen or alkyl (e.g., C1-C6 alkyl). In some embodiments, R 2 is haloalkyl (eg, C1-C6 haloalkyl).

[0144] In some embodiments, R 2 and R 3 Each of R is independently alkyl (e.g., substituted C1-C6 alkyl) or hydrogen. 2 and R 3 Each of R is independently unsubstituted alkyl (e.g., unsubstituted C1-C6 alkyl) or hydrogen. 2 and R 3 Each of R is independently C1-C6 haloalkyl (e.g., trifluoromethyl) or hydrogen. 2 and R 3 Each of R is independently hydrogen, carbocyclyl, or heterocyclyl. 2 and R 3 Each of R is independently C2-C6 alkyl (e.g., isopropyl or tert-butyl) or hydrogen. 2 and R 3 Each of is independently hydrogen or C3-C6 alkyl (e.g., isopropyl or tert-butyl).

[0145] In some embodiments, R 2 and R 3 at least one of R is C-C alkyl (e.g., isopropyl or tert-butyl), carbocyclyl, or heterocyclyl; or R 2 and R 3 together with the carbon atoms to which they are attached form a 3- to 8-membered ring. In some embodiments, R 2 is isopropyl or tert-butyl, and R 3 is methyl or hydrogen. In some embodiments, R 2is a substituted isopropyl or substituted tert-butyl, and R 3 is unsubstituted methyl or hydrogen. In some embodiments, R 2 is unsubstituted isopropyl or unsubstituted tert-butyl, and R 3 is unsubstituted methyl or hydrogen. In some embodiments, R 2 is tert-butyl, and R 3 is hydrogen. In some embodiments, R 2 is a substituted tert-butyl, and R 3 is hydrogen. In some embodiments, R 2 is unsubstituted tert-butyl, and R 3 is hydrogen. In some embodiments, R 2 is trifluoromethyl, and R 3 is hydrogen. In some embodiments, R 2 is trifluoromethyl, and R 3 is methyl. In some embodiments, R 2 is trifluoromethyl, and R 3 is substituted methyl. In some embodiments, R 2 is trifluoromethyl, and R 3 is unsubstituted methyl. In some embodiments, R 2 is methyl, and R 3 is hydrogen. In some embodiments, R 2 is a substituted methyl, and R 3 is hydrogen. In some embodiments, R 2 is unsubstituted methyl, and R 3 is hydrogen.

[0146] In some embodiments, R 4 is —OH or halo (e.g., —F). In some embodiments, R 4 and R 5 together with the carbon atom to which they are attached form an oxo group. In some embodiments, R 4is hydrogen, and R 5 is halo (e.g., -F). In some embodiments, R 4 and R 5 is halo (e.g., -F). In some embodiments, R 4 and R 5 is hydrogen.

[0147] In some embodiments, R 2 and R 3 together with the carbon atoms to which they are attached form a five-membered ring. 2 is C2-C6 alkyl (e.g., substituted or unsubstituted isopropyl or substituted or unsubstituted tert-butyl), and R 3 is C1-C6 alkyl (e.g., substituted or unsubstituted C1-C6 alkyl). In some embodiments, R 2 is unsubstituted C2-C6 alkyl (e.g., unsubstituted isopropyl or unsubstituted tert-butyl), and R 3 is unsubstituted C1-C6 alkyl. In some embodiments, R 2 and R 3 form a six-membered ring together with the carbon atoms to which they are attached.

[0148] In some embodiments, R 2 is carbocyclyl or heterocyclyl, and R 3 is hydrogen. In some embodiments, R 2 and R 3 is hydrogen. In some embodiments, R 2 is isopropyl, and R 3 is hydrogen. In some embodiments, R 2 is substituted isopropyl, and R 3 is hydrogen. In some embodiments, R 2 is substituted isopropyl, and R 3 is hydrogen. In some embodiments, R 2 and R 3together with the carbon atoms to which they are attached form a 3- to 8-membered carbocyclic ring (e.g., cyclohexyl) or heterocyclic ring (e.g., tetrahydrofuranyl or tetrahydropyranyl). In some embodiments, the carbocyclic or heterocyclic ring is substituted (e.g., a ring substituted with one or two halo or alkyl groups). In some embodiments, R 2 is cyclobutyl, and R 3 is hydrogen. In some embodiments, R 2 is tetrahydropyranyl, and R 3 is hydrogen.

[0149] In some embodiments, R 2 is a substituted cyclobutyl, and R 3 is hydrogen. In some embodiments, R 2 is a substituted tetrahydropyranyl, and R 3 is hydrogen. In some embodiments, R 2 is unsubstituted cyclobutyl, and R 3 is hydrogen. In some embodiments, R 2 is unsubstituted tetrahydropyranyl, and R 3 is hydrogen.

[0150] In some embodiments, the compound of formula (I-59) has formula (I-A59), (I-B59), or (I-C59): [ka] The compound is selected from the group consisting of:

[0151] In some embodiments, the compound of formula (I-59) has the formula (I-B59): [ka] The compound is selected from the group consisting of:

[0152] In some embodiments, the compound of formula (I-59) has the formula (I-C59): [ka] The compound is selected from the group consisting of:

[0153] In some embodiments, R 2 and R 3 at least one of R is hydrogen, C1-C6 alkyl, carbocyclyl, or heterocyclyl; or R 2 and R 3 together with the carbon atoms to which they are attached form a 3-8 membered ring. In some embodiments, the compound of formula (I-59) has the formula (I-D59): [ka] The compound is selected from the group consisting of:

[0154] In some embodiments, the compound of formula (I-59) has the formula (I-E59): [ka] The compound is selected from the group consisting of:

[0155] In some embodiments, the compound of formula (I-59) has the formula (ID-i59) or (ID-ii59): [ka] The compound is selected from the group consisting of:

[0156] In some embodiments, the compound of formula (I-59) has the formula (IE-i59) or (IE-ii59): [ka] The compound is selected from the group consisting of:

[0157] In some embodiments, the compound is [ka] [ka] is.

[0158] In one aspect, the compound of formula (I-66): [ka] [In the formula, R 1 is alkyl (e.g., C1-C6 alkyl); R 2 is aralkyl, heteroaralkyl, aryl, or heteroaryl; R 3 is hydrogen, alkyl (e.g., C1-C6 alkyl), carbocyclyl, heterocyclyl, aryl, or heteroaryl; R 4 and R 5 each independently represents hydrogen, halo, or -OR C where R C is hydrogen or C1-C3 alkyl (e.g., unsubstituted or substituted C1-C3 alkyl), or R 4 and R 5 form an oxo group together with the carbon atom to which they are attached; R 6 is absent or is hydrogen; and [ka] represents a single or double bond, where: [ka] If one of the is a double bond, the other [ka] is a single bond; [ka] If both are single bonds, R 6 is hydrogen; and [ka] If one of the groups is a double bond, R 6 is not present], or a pharmaceutically acceptable salt thereof.

[0159] In some embodiments, R 1 is alkyl (e.g., C1-C6 alkyl). In some embodiments, R 1 is C1-C6 alkyl (e.g., -CH3, -CH2CH3, -CH2OCH3, or -CF3). In some embodiments, R 1 is -CH, -CF, or -CHCH. In some embodiments, R 1 Ha-CH2OR A where R A is C1 to C6 alkyl (for example, C1 to C3 alkyl).

[0160] In some embodiments, R 2 is aryl (e.g., substituted or unsubstituted aryl, e.g., substituted or unsubstituted phenyl), heteroaryl (e.g., substituted or unsubstituted heteroaryl, e.g., substituted or unsubstituted pyridyl), or aralkyl (e.g., substituted or unsubstituted benzyl). In some embodiments, R 2 is phenyl (eg, substituted or unsubstituted phenyl), pyridyl (eg, substituted or unsubstituted pyridyl), or benzyl (eg, substituted or unsubstituted benzyl).

[0161] In some embodiments, R 3 is hydrogen or alkyl (e.g., C1-C6 alkyl). In some embodiments, R 3 is hydrogen, unsubstituted alkyl (eg, unsubstituted C1-C6 alkyl), or haloalkyl (eg, -CF3).

[0162] In some embodiments, R 4 is —OH or halo (e.g., —F).

[0163] In some embodiments, R 4 and R 5 together with the carbon atom to which they are attached form an oxo group. In some embodiments, R 4 is hydrogen, and R 5 is halo (e.g., -F). In some embodiments, R 4 and R 5 is halo (e.g., -F). In some embodiments, R 4 and R 5 is hydrogen.

[0164] In some embodiments, R 2 is aryl (e.g., substituted or unsubstituted aryl, e.g., substituted or unsubstituted phenyl), heteroaryl (e.g., substituted or unsubstituted heteroaryl, e.g., substituted or unsubstituted pyridyl), aralkyl (e.g., substituted or unsubstituted aralkyl, e.g., substituted or unsubstituted benzyl) or heteroaralkyl, and R 3 is hydrogen or alkyl (e.g., unsubstituted C1-C6 alkyl, e.g., C1-C6 haloalkyl). In some embodiments, R 2 is aryl (e.g., substituted or unsubstituted aryl, e.g., substituted or unsubstituted phenyl), heteroaryl (e.g., substituted or unsubstituted heteroaryl, e.g., substituted or unsubstituted pyridyl), aralkyl (e.g., substituted or unsubstituted aralkyl, e.g., substituted or unsubstituted benzyl) or heteroaralkyl, and R 3 is hydrogen, -CH3 or -CF3.

[0165] In some embodiments, R 1 is alkyl (e.g., C1-C6 alkyl), and R 2 is aryl (e.g., substituted or unsubstituted aryl, e.g., substituted or unsubstituted phenyl), heteroaryl (e.g., substituted or unsubstituted heteroaryl, e.g., substituted or unsubstituted pyridyl), aralkyl (e.g., substituted or unsubstituted aralkyl, e.g., substituted or unsubstituted benzyl) or heteroaralkyl, and R 3 is hydrogen, —CH or —CF. In some embodiments, R 1 is -CH3 or -CH2CH3, and R 2 is unsubstituted phenyl, unsubstituted pyridyl, or unsubstituted benzyl, and R 3 is hydrogen, -CH3 or -CF3.

[0166] In some embodiments, the compound of formula (I-66) has formula (I-A66), (I-B66), or (I-C66): [ka] The compound is selected from the group consisting of:

[0167] In some embodiments, the compound of formula (I-66) has the formula (I-A66): [ka] The compound is selected from the group consisting of:

[0168] In some embodiments, the compound is [ka] [ka] is.

[0169] In one aspect, the compound of formula (I-61): [ka] [In the formula, R 1 is hydrogen or alkyl (e.g., C1-C6 alkyl); R 2 and R 3 each is independently hydrogen, alkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, or R 2 and R3 form a 3- to 8-membered ring together with the carbon atoms to which they are attached; R 4 and R 5 each independently represents hydrogen, halo, or -OR C where R C is hydrogen or alkyl (e.g., C1-C6 alkyl), or R 4 and R 5 form an oxo group together with the carbon atom to which they are attached; R 6 is absent or is hydrogen; and [ka] represents a single or double bond, where: [ka] If one of the is a double bond, the other [ka] is a single bond; [ka] If both are single bonds, R 6 is hydrogen; and [ka] If one of the groups is a double bond, R 6 does not exist] or a pharmaceutically acceptable salt thereof [provided that the following compounds: [ka] [ka] are excluded] are provided herein.

[0170] In some embodiments, R 1 is alkyl (e.g., C1-C6 alkyl) or hydrogen. In some embodiments, R1 is C2-C6 alkyl (e.g., C3-C6 alkyl) or hydrogen. In some embodiments, R 1 is a substituted or unsubstituted C2-C6 alkyl (e.g., a substituted or unsubstituted C3-C6 alkyl) or hydrogen In some embodiments, R 1 is methyl or ethyl (e.g., substituted or unsubstituted methyl or substituted or unsubstituted ethyl). In some embodiments, R 1 is substituted or unsubstituted methyl or substituted or unsubstituted ethyl. In some embodiments, R 1 is trifluoromethyl. In some embodiments, R 1 Ha-CH2OR A where R A is C1 to C6 alkyl (for example, C1 to C3 alkyl).

[0171] In some embodiments, R 2 is hydrogen or C1-C6 alkyl (e.g., C2-C6 alkyl). In some embodiments, R 2 is hydrogen or substituted or unsubstituted C1-C6 alkyl (e.g., substituted or unsubstituted C2-C6 alkyl). In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is isopropyl (e.g., substituted or unsubstituted isopropyl). In some embodiments, R 2 is substituted or unsubstituted isopropyl. In some embodiments, R 2 is haloalkyl (eg, C1-C6 haloalkyl).

[0172] In some embodiments, R 2 and R 3 Each of R is independently alkyl (e.g., C1-C6 alkyl) or hydrogen. 2 and R 3Each of R is independently substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl) or hydrogen. 2 and R 3 together with the carbon atoms to which they are attached form a 3- to 8-membered ring. In some embodiments, R 2 and R 3 Each of is independently hydrogen or C1-C6 alkyl (e.g., C2-C6 alkyl). In some embodiments, R 2 and R 3 is independently hydrogen or substituted or unsubstituted C1-C6 alkyl (e.g., substituted or unsubstituted C2-C6 alkyl). 2 and R 3 Each of R is independently hydrogen or C-C alkyl (e.g., isopropyl). 2 and R 3 Each of is independently hydrogen or substituted or unsubstituted C3-C6 alkyl (eg, substituted or unsubstituted isopropyl).

[0173] In some embodiments, R 4 is —OH or halo (e.g., —F). In some embodiments, R 4 and R 5 together with the carbon atom to which they are attached form an oxo group. In some embodiments, R 4 is hydrogen, and R 5 is halo (e.g., -F). In some embodiments, R 4 and R 5 is halo (e.g., -F). In some embodiments, R 4 and R 5 is hydrogen.

[0174] In some embodiments, R 2 and R 3 is hydrogen. In some embodiments, R 2 is C1-C6 alkyl, and R 3is C2-C6 alkyl (e.g., C3-C6 alkyl). In some embodiments, R 2 is a substituted or unsubstituted C1-C6 alkyl, and R 3 is a substituted or unsubstituted C2-C6 alkyl (e.g., a substituted or unsubstituted C3-C6 alkyl). In some embodiments, R 1 is ethyl (e.g., substituted or unsubstituted ethyl), and R 2 and R 3 is methyl (e.g., substituted or unsubstituted methyl). In some embodiments, R 1 is substituted or unsubstituted ethyl, and R 2 and R 3 is substituted or unsubstituted methyl. In some embodiments, R 1 is ethyl, and R 2 is isopropyl, and R 3 is hydrogen. In some embodiments, R 1 is a substituted or unsubstituted ethyl, and R 2 is substituted or unsubstituted isopropyl, and R 3 is hydrogen. In some embodiments, R 1 is ethyl, and R 2 is isopropyl, and R 3 is methyl. In some embodiments, R 1 is a substituted or unsubstituted ethyl, and R 2 is substituted or unsubstituted isopropyl, and R 3 is substituted or unsubstituted methyl.

[0175] In some embodiments, the compound of formula (I-61) has formula (I-A61), (I-B61), or (I-C61): [ka] is a compound of

[0176] In some embodiments, the compound of formula (I-61) has the formula (I-C61): [ka] The compound is selected from the group consisting of:

[0177] In some embodiments, the compound of formula (I-61) has the formula (I-A61): [ka] The compound is selected from the group consisting of:

[0178] In some embodiments, the compound of formula (I-61) has the formula (IC-i61) or (IC-ii61): [ka] The compound is selected from the group consisting of: In some embodiments, the compound is [ka] is.

[0179] In one aspect, the present invention provides a compound of formula (I-62): [ka] [In the formula, R 1 is hydrogen or alkyl (e.g., C1-C6 alkyl); R 2 and R 3 each is independently hydrogen, alkyl, carbocyclyl, or heterocyclyl, or R 2 and R 3 form a 3- to 8-membered ring together with the carbon atoms to which they are attached; R 4 and R 5 each independently represents hydrogen, halo, or -OR C where R C is hydrogen or alkyl (e.g., C1-C6 alkyl), or R 4 and R 5 form an oxo group together with the carbon atom to which they are attached; R 6is absent or is hydrogen; and [ka] represents a single or double bond, where: [ka] If one of the is a double bond, the other [ka] is a single bond; [ka] If both are single bonds, R 6 is hydrogen; and [ka] If one of the groups is a double bond, R 6 is absent] or a pharmaceutically acceptable salt thereof.

[0180] In some embodiments, R 1 is alkyl (e.g., C1-C6 alkyl). In some embodiments, R 1 is a substituted or unsubstituted C2-C6 alkyl (e.g., a substituted or unsubstituted C3-C6 alkyl). In some embodiments, R 1 is methyl or ethyl (e.g., substituted or unsubstituted methyl or substituted or unsubstituted ethyl). In some embodiments, R 1 is substituted or unsubstituted methyl or substituted or unsubstituted ethyl. In some embodiments, R 1 is trifluoromethyl. In some embodiments, R 1 Ha-CH2OR A where R A is C1 to C6 alkyl (for example, C1 to C3 alkyl).

[0181] In some embodiments, R 2 is hydrogen or C1-C6 alkyl (e.g., C2-C6 alkyl). In some embodiments, R 2 is hydrogen or substituted or unsubstituted C1-C6 alkyl (e.g., substituted or unsubstituted C2-C6 alkyl). In some embodiments, R 2 is haloalkyl (eg, C1-C6 haloalkyl).

[0182] In some embodiments, R 2 and R 3 Each of is independently hydrogen or C1-C6 alkyl (e.g., C2-C6 alkyl). In some embodiments, R 2 and R 3 is independently hydrogen or substituted or unsubstituted C1-C6 alkyl (e.g., substituted or unsubstituted C2-C6 alkyl). 2 and R 3 Each of R is independently alkyl (e.g., C1-C6 alkyl) or hydrogen. 2 and R 3 Each of R is independently substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl) or hydrogen. 2 and R 3 form a 3- to 8-membered ring together with the carbon atoms to which they are attached.

[0183] In some embodiments, R 4 is —OH or halo (e.g., —F). In some embodiments, R 4 and R 5 together with the carbon atom to which they are attached form an oxo group. In some embodiments, R 4 is hydrogen, and R 5 is halo (e.g., -F). In some embodiments, R 4 and R 5 is halo (e.g. , -F). In some embodiments, R 4 and R 5 is hydrogen.

[0184] In some embodiments, R 1 is ethyl (e.g., substituted or unsubstituted ethyl), and R 2 and R 3 is methyl (e.g., substituted or unsubstituted methyl). In some embodiments, R 1 is substituted or unsubstituted ethyl, and R 2 and R 3 is substituted or unsubstituted methyl.

[0185] In some embodiments, the compound of formula (I-62) has formula (I-A62), (I-B62), or (I-C62): [ka] is a compound of

[0186] In some embodiments, the compound of formula (I-62) has the formula (I-C62): [ka] The compound is selected from the group consisting of:

[0187] In some embodiments, the compound of formula (I-62) has the formula (I-A62): [ka] The compound is selected from the group consisting of:

[0188] In some embodiments, R 1 is ethyl (e.g., substituted or unsubstituted ethyl), and R 2 and R 3 is methyl (e.g., substituted or unsubstituted methyl). In some embodiments, R 1 is substituted or unsubstituted ethyl, and R 2and R 3 is substituted or unsubstituted methyl.

[0189] In some embodiments, the compound of formula (I-62) has the formula (IC-i62) or (IC-ii62): [ka] The compound is selected from the group consisting of:

[0190] In some embodiments, the compound is [ka] is.

[0191] In one aspect, the compound of formula (I-60): [ka] [In the formula, R 2 and R 3 each is independently hydrogen, alkyl (e.g., C1-C6 alkyl), carbocyclyl, heterocyclyl, aryl, or heteroaryl, or R 2 and R 3 form a 3- to 8-membered ring together with the carbon atoms to which they are attached; R 4 and R 5 each independently represents hydrogen, halo, or -OR C where R C is hydrogen or alkyl (e.g., C1-C6 alkyl), or R 4 and R 5 form an oxo group together with the carbon atom to which they are attached; R 6 is absent or is hydrogen; and [ka] represents a single or double bond, where: [ka] If one of the is a double bond, the other [ka] is a single bond; [ka] If both are single bonds, R 6 is hydrogen; and [ka] If one of the groups is a double bond, R 6 is not present], or a pharmaceutically acceptable salt thereof. In some embodiments, R 2 is alkyl (e.g., C1-C6 alkyl) or hydrogen. In some embodiments, R 2 is haloalkyl (e.g., C1-C6 haloalkyl). In some embodiments, R 2 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl) or hydrogen. In some embodiments, R 2 is aryl or heteroaryl. In some embodiments, R 2 and R 3 Each of R is independently alkyl (e.g., C1-C6 alkyl) or hydrogen. 2 and R 3 Each of R is independently substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl) or hydrogen. 2 and R 3 Each of R is independently unsubstituted alkyl (e.g., unsubstituted C1-C6 alkyl) or hydrogen. 2 and R 3 Each of R is independently C1-C6 haloalkyl (e.g., trifluoromethyl) or hydrogen. 2 and R 3Each of R is independently aryl or heteroaryl. 2 and R 3 form a three-membered ring together with the carbon atoms to which they are attached. In some embodiments, R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropane. In some embodiments, R 2 and R 3 together with the carbon atoms to which they are attached form a 3- to 8-membered carbocyclic or heterocyclic ring. In some embodiments, R 2 is carbocyclyl or heterocyclyl, and R 3 is hydrogen. In some embodiments, R 2 is trifluoromethyl, and R 3 is hydrogen. In some embodiments, R 2 is aryl or heteroaryl, and R 3 is hydrogen. In some embodiments, R 2 and R 3 is methyl (e.g., substituted or unsubstituted methyl). In some embodiments, R 2 and R 3 is substituted methyl. In some embodiments, R 2 and R 3 is unsubstituted methyl. In some embodiments, R 4 is —OH or halo (e.g., —F). In some embodiments, R 4 and R 5 together with the carbon atom to which they are attached form an oxo group. In some embodiments, R 4 is hydrogen, and R 5 is halo (e.g., -F). In some embodiments, R 4 and R 5 is halo (e.g., -F). In some embodiments, R 4 and R5 is hydrogen. In some embodiments, the compound of formula (I-60) has formula (I-A60), (I-B60), or (I-C60): [ka] The compound is selected from the group consisting of: In some embodiments, the compound of formula (I-60) has the formula (I-B60): [ka] The compound is selected from the group consisting of: In some embodiments, R 2 and R 3 at least one of is C1-C6 alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R 2 and R 3 form a 3- to 8-membered ring together with the carbon atoms to which they are attached. In some embodiments, R 2 is methyl, and R 3 is hydrogen. In some embodiments, R 2 is unsubstituted methyl, and R 3 is hydrogen. In some embodiments, R 2 and R 3 is hydrogen. In some embodiments, the compound is [ka] is.

[0192] In alternative embodiments, the compounds 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, 18O; nitrogen can be, for example, 15 N, etc. In other embodiments, a specific isotope (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 particular site on the compound. Pharmaceutical Compositions

[0193] In another aspect, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and an effective amount of a compound of Formula I-59, I-66, I-61, I-62, or I-60.

[0194] When used as pharmaceuticals, the compounds provided herein are typically administered in the form of a pharmaceutical composition, which can be prepared in a manner well known in the pharmaceutical arts and can contain at least one active compound.

[0195] In one embodiment, with respect to a pharmaceutical composition, the carrier is a parenteral carrier, an oral carrier, or a topical carrier.

[0196] The present invention also relates to a compound of formula I-59, I-66, I-61, I-62 or I-60, or a pharmaceutical composition thereof, for use as a medicine or medicament.

[0197] Generally, the compounds provided herein are administered in effective amounts. The amount of an agent will typically be determined by a physician in light of the relevant circumstances (including the condition being treated, the selected route of administration, the actual compound being administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.).

[0198] The pharmaceutical compositions provided herein can be administered by various routes, including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Depending on the intended delivery route, the compounds provided herein are preferably formulated as either injectable or oral compositions, or as ointments, lotions, or patches (all for transdermal administration).

[0199] Compositions for oral administration can take the form of bulk liquid solutions or suspensions or bulk powders. However, more commonly, compositions are provided in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined amount of active ingredient calculated to produce a desired therapeutic effect, together with suitable pharmaceutical excipients. Typical unit dosage forms include pre-measured, pre-filled ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc., for solid compositions. In such compositions, the compound is usually a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder consisting of various vehicles or carriers and processing aids useful in forming the desired dosage form.

[0200] Liquid forms suitable for oral administration include buffers, suspensions and dispensing preparations. The formulation may comprise a suitable aqueous or non-aqueous vehicle containing additives, colorants, flavoring agents, etc. Solid forms may contain, for example, any of the following ingredients, or compounds of a similar nature: binders (e.g., microcrystalline cellulose, gum tragacanth, or gelatin); fillers (e.g., starch or lactose); disintegrating agents (e.g., alginic acid, Primogel, or corn starch); lubricants (e.g., magnesium stearate); glidants (e.g., colloidal silicon dioxide); sweetening agents (e.g., sucrose or saccharin); or flavoring agents (e.g., peppermint, methyl salicylate, or orange flavoring).

[0201] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. Conventionally, the active compound in such compositions is typically a minor component, often about 0.05 to 10% by weight, with the remainder being the injectable carrier and the like.

[0202] Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, more preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredient is typically combined with a paraffinic or water-miscible ointment base. Alternatively, the active ingredient can be formulated as a cream, for example, with an oil-in-water cream base. Such transdermal formulations are well known in the art and generally include additional ingredients that enhance the skin penetration or stability of the active ingredient or formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.

[0203] The compounds provided herein can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type or of a solid matrix variety.

[0204] Orally administrable, injectable, or topically administrable compositions are described above. The components shown are merely representative. Other materials, processing techniques, etc. are set forth in Part 8 of Remington's Pharmaceutical Sciences, 17th Edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0205] The components described above for orally administrable, injectable, or topically administrable compositions are merely representative. Other materials, processing techniques, and the like are set forth in Part 8 of Remington's The Science and Practice of Pharmacy, 21st Edition, 2005, published by Lippincott Williams & Wilkins, which is incorporated herein by reference.

[0206] The compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0207] The present invention also relates to pharmaceutically acceptable formulations of compounds of formula I-59, I-66, I-61, I-62, or I-60. In one embodiment, the formulation contains water. In another embodiment, the formulation contains a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, which consist of six, seven, and eight α-1,4-linked glucose units, respectively, optionally containing one or more substituents on the linked sugar moiety, including, but not limited to, methylation, hydroxyalkylation, acylation, and sulfoalkyl ether substitution. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, also known as Captisol®. See, e.g., U.S. Pat. No. 5,376,645. In certain embodiments, the formulation contains hexapropyl-β-cyclodextrin. In further specific embodiments, the formulation includes hexapropyl-β-cyclodextrin (eg, 10-50% in water).

[0208] The present invention also relates to pharmaceutically acceptable acid addition salts of compounds of Formula I-59, I-66, I-61, I-62, or I-60. Acids that can be used to prepare pharmaceutically acceptable salts are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions (e.g., hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, and the like).

[0209] The following formulation examples illustrate representative pharmaceutical compositions that may be prepared in accordance with the present invention, although the present invention is not limited to the following pharmaceutical compositions.

[0210] Exemplary Formulation 1—Tablets: A compound of Formula I-59, I-66, I-61, I-62, or I-60, or a pharmaceutically acceptable salt thereof, can be blended as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A trace amount of magnesium stearate is added as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg of active compound per tablet) in a tablet press.

[0211] Exemplary Formulation 2—Capsules: A compound of Formula I-59, I-66, I-61, I-62, or I-60, or a pharmaceutically acceptable salt thereof, can be mixed as a dry powder with a starch diluent in an approximately 1:1 weight ratio. The mixture is filled into 250 mg capsules (125 mg of active compound per capsule).

[0212] Exemplary Formulation 3 - Liquid: A compound of Formula I-59, I-66, I-61, I-62, or I-60, or a pharmaceutically acceptable salt thereof (125 mg) can be mixed with sucrose (1.75 g) and xanthan gum (4 mg), and the resulting mixture can be blended and passed through a No. 10 mesh US sieve, then mixed with a previously prepared aqueous solution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50 mg). Sodium benzoate (10 mg), flavor, and color can be diluted with water and added with stirring. Sufficient water can then be added to bring the total volume to 5 mL.

[0213] Exemplary Formulation 4—Tablets: A compound of Formula I-59, I-66, I-61, I-62, or I-60, or a pharmaceutically acceptable salt thereof, can be blended as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A trace amount of magnesium stearate is added as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg of active compound) in a tablet press.

[0214] Exemplary Formulation 5—Injection: A compound of Formula I-59, I-66, I-61, I-62 or I-60, or a pharmaceutically acceptable salt thereof, can be dissolved or suspended in a sterile buffered saline injectable aqueous medium to a concentration of approximately 5 mg / mL.

[0215] Exemplary Formulation 6—Tablets: A compound of Formula I-59, I-66, I-61, I-62, or I-60, or a pharmaceutically acceptable salt thereof, can be blended as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A trace amount of magnesium stearate is added as a lubricant. The mixture is formed into 90-150 mg tablets (30-50 mg of active compound per tablet) in a tablet press.

[0216] Exemplary Formulation 7—Tablets: A compound of Formula I-59, I-66, I-61, I-62, or I-60, or a pharmaceutically acceptable salt thereof, can be blended as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A trace amount of magnesium stearate is added as a lubricant. The mixture is formed into 30-90 mg tablets (10-30 mg of active compound per tablet) in a tablet press.

[0217] Exemplary Formulation 8—Tablets: A compound of Formula I-59, I-66, I-61, I-62, or I-60, or a pharmaceutically acceptable salt thereof, can be blended as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A trace amount of magnesium stearate is added as a lubricant. The mixture is formed into 0.3-30 mg tablets (0.1-10 mg of active compound per tablet) in a tablet press.

[0218] Exemplary Formulation 9—Tablets: A compound of Formula I-59, I-66, I-61, I-62, or I-60, or a pharmaceutically acceptable salt thereof, can be blended as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A trace amount of magnesium stearate is added as a lubricant. The mixture is formed into 150-240 mg tablets (50-80 mg of active compound per tablet) in a tablet press.

[0219] Exemplary Formulation 10—Tablets: A compound of Formula I-59, I-66, I-61, I-62, or I-60, or a pharmaceutically acceptable salt thereof, can be blended as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A trace amount of magnesium stearate is added as a lubricant. The mixture is formed into 270-450 mg tablets (90-150 mg of active compound per tablet) in a tablet press.

[0220] Injectable dosage levels range from about 0.1 mg / kg / hour to at least 10 mg / kg / hour. The doses range from about 1 to about 120 hours, particularly 24 to 96 hours. A preloading bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady-state levels. The maximum total dose is not expected to exceed about 2 g / day for a 40-80 kg human patient.

[0221] For the prevention and / or treatment of long-term conditions, the regimen usually extends over many months or years, and oral administration is preferred for patient convenience and tolerance. For oral administration, oral administration 1 to 5 times per day, particularly 2 to 4 times per day, typically 3 times per day is a typical regimen. Using these dosing patterns, each dose provides about 0.01 to about 20 mg / kg of a compound provided herein, with preferred doses providing about 0.1 to about 10 mg / kg, particularly about 1 to about 5 mg / kg, respectively.

[0222] Transdermal administration is generally selected to provide blood levels similar to or lower than those achieved using injection administration.

[0223] When used to prevent the occurrence of CNS disorders, the compounds provided herein can typically be administered to subjects at risk of developing the condition at the dosage levels described above, under the advice and supervision of a physician. Subjects at risk of developing a particular condition generally include subjects with a family history of the condition, or subjects identified by genetic testing or screening as being particularly susceptible to developing the condition. Treatment Methods and Uses

[0224] The compounds of the invention described herein (e.g., compounds of formula I-59, I-66, I-61, I-62, or I-60) and pharmaceutically acceptable salts thereof can be used in a method of achieving positive allosteric modulation of a PMDA receptor in a subject in need thereof, comprising administering to the subject a compound that achieves negative allosteric modulation of an NMDA receptor in a subject in need thereof, and administering to the subject a compound of formula I-59, I-66, I-61, I-62, or I-60.

[0225] The compounds of the present invention (e.g., compounds of formula I-59, I-66, I-61, I-62, or I-60) and pharmaceutically acceptable salts thereof, as described herein, are generally designed to modulate NMDA function and thus act as oxysterols for the treatment and prevention of, for example, CNS-related conditions in a subject. In some embodiments, the compounds described herein (e.g., compounds of formula I-59, I-66, I-61, I-62, or I-60) and pharmaceutically acceptable salts thereof, as described herein, are generally designed to penetrate the blood-brain barrier (e.g., designed to be transported across the blood-brain barrier). Modulation, as used herein, refers, for example, to the inhibition or potentiation of NMDA receptor function. In certain embodiments, a compound of Formula I-59, I-66, I-61, I-62, or I-60, or a pharmaceutically acceptable salt thereof, acts as an NMDA negative allosteric modulator (NAM) and inhibits NMDA receptor function. In certain embodiments, a compound of the present invention (e.g., a compound of Formula I-59, I-66, I-61, I-62, or I-60, or a pharmaceutically acceptable salt thereof) acts as an NMDA positive allosteric modulator (PAM) and potentiates NMDA receptor function. In certain embodiments, a compound of Formula I-59, I-66, I-61, I-62, or I-60, or a pharmaceutically acceptable salt thereof, blocks or reduces the potentiation or inhibition of NMDA receptor function by naturally occurring substrates. Such compounds may function both as NMDA negative allosteric modulators (NAMs) and as NMDA positive allosteric modulators (PAMs). In some embodiments, the disorder does not act as a steroid hormone receptor antagonist. In some embodiments, the disorder is cancer. In some embodiments, the disorder is diabetes. In some embodiments, the disorder is a sterol synthesis disorder. In some embodiments, the disorder is a gastrointestinal (GI) disorder, such as constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) (e.g., ulcerative colitis, Crohn's disease), a structural disorder affecting the GI, anal disorders (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas), colon polyps, cancer, or colitis. In some embodiments, the disorder is inflammatory bowel disease.

[0226] Exemplary conditions associated with NMDA modulation include, but are not limited to, gastrointestinal (GI) disorders (e.g., constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) (e.g., ulcerative colitis, Crohn's disease), structural disorders affecting the GI, anal disorders (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas), colon polyps, cancer, colitis), and CNS conditions (e.g., as described herein).

[0227] Exemplary conditions (e.g., CNS conditions) associated with NMDA modulation include adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, social phobia, generalized anxiety disorder), cognitive disorders (including Alzheimer's disease and other forms of dementia, including corticobasal dementia progressive supranuclear palsy, frontotemporal dementia, primary progressive aphasia, Parkinson's disease dementia, and dementia with Lewy bodies), dissociative disorders, eating disorders, mood disorders (including depression, e.g., postpartum depression, bipolar disorder, dysthymic disorder, suicidality), schizophrenia or other psychotic disorders (including schizoaffective psychosis), sleep disorders (including insomnia), substance abuse-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those containing mutations in the Shank family of proteins, e.g., Shank3). Neurodevelopmental disorders (including Rett syndrome), multiple sclerosis, sterol synthesis disorders, Smith-Lemli-Opitz syndrome, pain (including acute pain, chronic pain, and neuropathic pain), seizure disorders (including status epilepticus and monogenic forms of epilepsy, such as Dravet disease, tuberous sclerosis complex (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 titer anti-NMDA receptor antibodies (including anti-NMDA receptor encephalitis), neurodegenerative disorders, neuroinflammation, neuropsychiatric lupus, Niemann-Pick C disorder, and tinnitus.

[0228] In certain embodiments, compounds of the invention, such as compounds of Formula I-59, I-66, I-61, I-62, or I-60, or pharmaceutically acceptable salts thereof, may be used to induce sedation or anesthesia.

[0229] In certain embodiments, the compound of Formula I-59, I-66, I-61, I-62, or I-60, or a pharmaceutically acceptable salt thereof, is used to treat 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 corticobasal dementia progressive supranuclear palsy, frontotemporal dementia, primary progressive aphasia, Parkinson's disease dementia, and dementia with Lewy bodies), dissociative disorders, eating disorders, mood disorders (including depression, e.g., postpartum depression, bipolar disorder, dysthymic disorder, suicidality), schizophrenia or other psychotic disorders (including schizoaffective psychosis), sleep disorders (including insomnia), substance abuse-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those containing mutations in the Shank family of proteins, e.g., Shank3), neurodevelopmental disorders, and the like. and tinnitus), neurodegenerative disorders (including Rett syndrome), multiple sclerosis, disorders of sterol synthesis, Smith-Lemli-Opitz syndrome, pain (including acute pain, chronic pain, and neuropathic pain), seizure disorders (including status epilepticus and monogenic forms of epilepsy, such as Dravet disease, tuberous sclerosis complex (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 titer anti-NMDA receptor antibodies (including anti-NMDA receptor encephalitis), neurodegenerative disorders, neuroinflammation, neuropsychiatric lupus, Niemann-Pick C disorder, and tinnitus.

[0230] In certain embodiments, compounds of Formula I-59, I-66, I-61, I-62, or I-60, or pharmaceutically acceptable salts thereof, are useful in the treatment or prevention of adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, social phobia, generalized anxiety disorder), cognitive disorders (including Alzheimer's disease and other forms of dementia, including corticobasal dementia progressive supranuclear palsy, frontotemporal dementia, primary progressive aphasia, Parkinson's disease dementia, and dementia with Lewy bodies)), substance abuse-related disorders, dissociative disorders, eating disorders, mood disorders (including depression (e.g., postpartum depression), bipolar disorder, dysthymic disorder, suicidality), schizophrenia or other psychotic disorders (including schizoaffective psychosis), personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those containing mutations in the Shank family of proteins (e.g., Shank3)), or postpartum psychosis.

[0231] In certain embodiments, a compound of Formula I-59, I-66, I-61, I-62, or I-60, or a pharmaceutically acceptable salt thereof, is useful in the treatment or prevention of neurodevelopmental disorders (including Rett syndrome), multiple sclerosis, sterol synthesis disorders, Smith-Lemli-Opitz syndrome, pain (including acute pain, chronic pain, and neuropathic pain), seizure disorders (including status epilepticus and monogenic forms of epilepsy, such as Dravet disease, tuberous sclerosis complex (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), syndromes associated with high titer anti-NMDA receptor antibodies (including anti-NMDA receptor encephalitis), neurodegenerative disorders, neuroinflammation, neuropsychiatric lupus, Niemann-Pick C disorder, or tinnitus.

[0232] In some embodiments, the compounds of the invention, e.g., PAMs of NMDA receptor function, Compounds of Formula I-59, I-66, I-61, I-62 or I-60 acting as a agonist may be useful in the treatment or prevention of conditions (e.g., CNS-related conditions) including schizophrenia or other psychotic disorders (including schizoaffective psychosis), sleep disorders (including insomnia), autism spectrum disorders (including those containing mutations to the Shank family of proteins (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).

[0233] In some embodiments, the compounds of the invention, e.g., NAMs, inhibit NMDA receptor function. The compounds of formula I-59, I-66, I-61, I-62 or I-60, which act as a medicament for the treatment of 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, dysthymic disorder, suicidality), personality disorders (including obsessive-compulsive personality disorder), neurodevelopmental disorders (including Rett syndrome), pain (including acute and chronic pain), seizure disorders (status epilepticus), These compounds may be useful in the treatment or prevention of conditions (e.g., CNS-related conditions) including epilepsy (including, for example, Dravet's disease, tuberous sclerosis complex (TSC), and infantile spasms), stroke, traumatic brain injury, adjustment disorder, neuropsychiatric lupus, and tinnitus.

[0234] In some embodiments, the compounds of the invention, e.g., PAMs or or compounds of formula I-59, I-66, I-61, I-62 or I-60 acting as NAMs. The products may be useful in the treatment or prevention of conditions (e.g., CNS-related conditions) including cognitive disorders (including Alzheimer's disease and other forms of dementia (including corticobasal dementia progressive supranuclear palsy, frontotemporal dementia, primary progressive aphasia, Parkinson's disease dementia, and dementia with Lewy bodies)), sterol synthesis disorders, and eating disorders.

[0235] In another aspect, a method is provided for treating or preventing brain excitability in a subject suspected of or afflicted with a condition associated with brain excitability, comprising administering to the subject an effective amount of a compound of the invention (e.g., a compound of formula I-59, I-66, I-61, I-62, or I-60, or a pharmaceutically acceptable salt thereof).

[0236] In yet another aspect, a combination of a compound of the present invention (e.g., a compound of Formula I-59, I-66, I-61, I-62, or I-60, or a pharmaceutically acceptable salt thereof) with another pharmacologically active agent is provided. The compounds provided herein can be administered as the sole active agent or in combination with other agents. The administration of the combination can proceed by any technique apparent to one skilled in the art (e.g., separate administration, sequential administration, simultaneous administration, and alternating administration). Movement disorders

[0237] Also described herein is the method for treating movement disorders.As used herein, " movement disorders " refers to various diseases and disorders related to hyperkinesia and related abnormalities in muscle control.Exemplary movement disorders include but are not limited to Parkinson's disease and paralysis (particularly defined by bradykinesia), dystonia, chorea and Huntington's disease, ataxia, tremor (for example, essential tremor), myoclonus and startle, tic and Tourette's syndrome, restless leg syndrome, stiff person syndrome and gait disorder.

[0238] Tremor is an involuntary, sometimes rhythmic, contraction and relaxation of muscles that may involve vibration or spasm of one or more body parts (e.g., hands, arms, eyes, face, head, vocal cords, trunk, legs). Tremor includes genetic, degenerative, and idiopathic disorders, such as Wilson's disease, Parkinson's disease, and essential tremor, respectively; metabolic diseases (e.g., thyroid-parathyroid disease, liver disease, and hypoglycemia); peripheral neuropathies (associated with Charcot-Marie-Tooth disease, Lucy-Lewy disease, diabetes mellitus, and complex regional pain syndrome); disorders induced by toxins (nicotine, mercury, lead, CO, manganese, arsenic, toluene); disorders induced by drugs (hypnotics, tricyclics, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremor can be classified into physiological tremor, fatigue-induced physiological tremor (enhanced physiologic tremor), essential tremor syndrome (including classic essential tremor, primary orthostatic tremor, and task-specific and position-specific tremor), dystonic tremor, Parkinson's tremor, cerebellar tremor, Holmes' tremor (i.e., red nucleus tremor), palatal tremor, neuropathic tremor, toxic or drug-induced tremor, and psychogenic tremor. Other forms of tremor include cerebellar or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, Parkinson's tremor, physiological tremor, psychogenic tremor, or red nucleus tremor.

[0239] Cerebellar tremor, or intention tremor, is a slow, widespread tremor of the limbs that occurs after a purposeful movement. Cerebellar tremor is caused by lesions in or damage to the cerebellum, for example, due to tumors, stroke, or disease (e.g., multiple sclerosis, inherited degenerative disorders).

[0240] Dystonic tremor occurs in individuals suffering from dystonia, a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive movements and / or painful abnormal postures or positions. Dystonic tremor can affect any muscle in the body. Dystonic tremor occurs irregularly and can often be relieved by complete rest.

[0241] Essential tremor, or benign essential tremor, is the most common type of tremor. Essential tremor can be mild and non-progressive in some cases, or it can be slowly progressive, starting on one side of the body but affecting both sides within three years. The hands are most frequently affected, but the head, voice, tongue, legs, and trunk can also be involved. Tremor frequency can decrease with age, but severity can increase. Emotional excitement, stress, fever, physical fatigue, or hypoglycemia can trigger tremor and / or increase its severity. Symptoms generally develop over a long period of time and can become visible and persist after onset.

[0242] Orthostatic tremor is characterized by rapid (e.g., greater than 12 Hz) rhythmic muscle contractions in the legs and trunk immediately after standing. Spasms are felt in the thighs and legs, and patients may tremble uncontrollably when asked to stand in one position. Orthostatic tremor can occur in patients with essential tremor.

[0243] Parkinsonian tremor is caused by damage to structures in the brain that control movement. Parkinsonian tremor is often a precursor to Parkinson's disease and is typically seen as a "pill-rolling" movement of the hand, and can also affect the chin, lips, legs, and trunk. The onset of Parkinsonian tremor typically begins after age 60. Movements may begin in one limb or one side of the body and progress to the other side.

[0244] Physiologic tremor can occur in normal individuals and has no clinical significance. Physiologic tremor can be seen in all voluntary muscle groups. Physiologic tremor can be caused by certain drugs, alcohol withdrawal, or medical conditions including hyperthyroidism and hypoglycemia. This tremor classically has a frequency of approximately 10 Hz.

[0245] Psychogenic or hysterical tremor can occur at rest or during postural or active movement. Patients with psychogenic tremor may have conversion disorder or another psychiatric illness.

[0246] Red nucleus tremor is characterized by slow, coarse tremors that can be present at rest, during posture, and with intention. This tremor may be related to conditions affecting the red nucleus in the classical and rare strokes of the midbrain.

[0247] Parkinson's disease affects the nerve cells in the brain that produce dopamine. Symptoms include muscle rigidity, tremor, and changes in speech and gait. Paresis tremens is characterized by tremor, bradykinesia, rigidity, and postural instability. Paresis tremens shares symptoms with Parkinson's disease, but is a group of conditions rather than a progressive neurodegenerative disease.

[0248] Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions that cause abnormal and often repetitive movements or postures. Dystonic movements can be patterned, twisting, or tremulous. Dystonias can be evoked or triggered by voluntary movements. It often worsens and is often associated with an overflow of muscle activation.

[0249] Chorea is a neurological disorder characterized by rhythmic involuntary movements that typically affect the shoulders, buttocks, and face.

[0250] Huntington's disease is a genetic disorder that weakens nerve cells in the brain. Symptoms include uncontrollable movements, clumsiness, and balance problems. Huntington's disease can interfere with walking, speaking, and swallowing.

[0251] Ataxia refers to the loss of complete control of bodily movements and can affect fingers, hands, arms, legs, body, speech and eye movements.

[0252] Myoclonus and startle are reactions to sudden and unexpected stimuli, which can be auditory, tactile, visual or vestibular.

[0253] Tics are involuntary movements that usually occur suddenly, are brief, repetitive, but not rhythmic, and typically mimic normal behaviors and often occur outside the background of normal activity. Tics can be classified as motor or vocal, with motor tics being associated with movement and vocal tics being associated with sound. Tics can also be characterized as simple or complex. For example, simple motor tics involve only a few muscles that are limited to a specific body part.

[0254] Tourette's syndrome is a childhood-onset, inherited neuropsychiatric disorder characterized by multiple motor tics and at least one vocal tic.

[0255] Restless legs syndrome is a neurological sensorimotor disorder characterized by an irresistible urge to move the legs while at rest.

[0256] Stiff-person syndrome is a progressive movement disorder characterized by involuntary, painful spasms and muscle stiffness, usually involving the lower back and legs. It typically presents with a stiff gait accompanied by excessive lumbar hyperlordosis. It typically presents with characteristic abnormalities in EMG recordings of continuous motor unit activity of paraspinal axial muscles. Variants include "stiff-limb syndrome," which typically affects the distal legs and feet, resulting in focal stiffness.

[0257] Gait disorders refer to abnormalities in the manner or style of walking due to neuromuscular, arthritic, or other physical changes. Gaits are classified according to systems relating to abnormal locomotion, including hemiplegic gait, diplegic gait, neuropathic gait, myopathic gait, parkinsonian gait, choreiform gait, ataxic gait, and sensory gait. Mood disorders

[0258] Also provided herein are methods for treating mood disorders, such as clinical depression, postpartum or postpartum depression, perinatal depression, atypical depression, melancholic depression, psychogenic major depression, catatonic depression, seasonal affective disorder, dysthymia, double depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar disorder or manic-depressive disorder, depression caused by a chronic medical condition, treatment-resistant depression, refractory depression, suicide, suicidal ideation, or suicidal behavior.

[0259] Clinical depression includes major depression, major depressive disorder (MDD), severe depression, unipolar depression, Also known as unipolar disorder and recurrent depression, it refers to a mental disorder characterized by a pervasive and persistent depressed mood, accompanied by low self-esteem and a loss of interest or pleasure in activities that are usually enjoyable.Some people with clinical depression have difficulty sleeping, become thin, generally feel agitated, and become irritable.Clinical depression affects how individuals feel, think, and behave, and can lead to a variety of emotional and physical problems.Individuals with clinical depression may have difficulty performing daily activities and may feel as if life is not worth living.

[0260] Postpartum depression (PND), also known as postpartum depression (PPD), refers to a type of clinical depression that women suffer from after giving birth.Symptoms may include sadness, fatigue, changes in sleep and eating habits, decreased sexual desire, crying episodes, anxiety and irritability.In some embodiments, PND is treatment-resistant depression (for example, treatment-resistant depression as described herein).In some embodiments, PND is treatment-refractory depression (for example, treatment-refractory depression as described herein).

[0261] In some embodiments, the subject with PND also experiences depression or symptoms of depression during pregnancy.This depression is referred to herein as perinatal depression.In some embodiments, the subject who experiences perinatal depression has a high risk of experiencing PND.

[0262] Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anhedonia) and aggressiveness, significant weight gain, or increased appetite. Patients with AD may also have significant social impairment as a result of excessive sleep or somnolence (hypersomnia), a feeling of heaviness in the limbs, and hypersensitivity to perceived interpersonal rejection.

[0263] Melancholic depression is characterized by loss of pleasure in most or all activities (anhedonia), unresponsiveness to pleasurable stimuli, a depressed mood that is more pronounced than a mood of sadness or loss, excessive weight loss, or excessive feelings of guilt.

[0264] Psychotic major depression (PMD) or psychotic depression refers to a major depressive episode, particularly one of a melancholic nature, in which an individual experiences psychotic symptoms such as delusions and hallucinations.

[0265] Catatonic depression refers to major depression accompanied by disturbances in motor behavior and other symptoms. Individuals may become mute and stuporous, become immobile, or exhibit aimless or bizarre movements.

[0266] Seasonal affective disorder (SAD) refers to a type of seasonal depression in which an individual has a seasonal pattern of depressive episodes that begin occurring in the fall or winter.

[0267] Dysthymia refers to a condition related to unipolar depression in which the same physical and cognitive problems are evident, although they tend to be less severe and last longer (e.g., at least 2 years).

[0268] Dual depression refers to a severely depressed mood (dysthymia) lasting at least two years and interrupted by periods of major depression.

[0269] Depressive personality disorder (DPD) refers to a personality disorder with depressive features.

[0270] Recurrent Brief Depression (RB) D) refers to a condition in which an individual has depressive episodes about once a month, with each episode lasting two weeks or less, typically less than two to three days.

[0271] Minor depressive disorder or minor depression refers to depression in which at least two symptoms are present for two weeks.

[0272] Bipolar disorder or manic-depressive disorder causes extreme mood swings, including high affect (mania or hypomania) and low affect (depression). During manic periods, individuals may feel or act unusually happy, energetic, or irritable. They often make thoughtless decisions with little regard for consequences. They usually have a decreased need for sleep. During depressive periods, individuals may cry uncontrollably, make less eye contact with others, and have a negative outlook on life. The risk of suicide for people with this disorder is high—more than 6% over a 20-year period—and 30–40% will engage in self-harm. Other mental health problems, such as anxiety disorders and substance use disorders, commonly coexist with bipolar disorder.

[0273] Chronic condition-induced depression refers to depression caused by a chronic medical condition such as cancer or chronic pain, chemotherapy, or chronic stress.

[0274] Treatment-resistant depression refers to the state that individuals are treated for depression but their symptoms do not improve.For example, antidepressants or psychological counseling (psychotherapy) do not alleviate the depressive symptoms of individuals with treatment-resistant depression.In some cases, individuals with treatment-resistant depression improve their symptoms, but then return.Treatment-resistant depression occurs in patients with depression that is resistant to standard pharmacological treatments, including tricyclic antidepressants, MAOIs, SSRIs, and double and triple uptake inhibitors, and / or anxiolytics, and non-pharmacological treatments (for example, psychotherapy, electroconvulsive therapy, vagus nerve stimulation and / or transcranial magnetic stimulation).

[0275] Suicidal tendencies, ideation, and behavior refer to an individual's tendency to commit suicide. Suicidal ideation involves thoughts about or an abnormal obsession with suicide. The spectrum of suicidal ideation varies widely, from fleeting thoughts to extensive thinking, detailed plans, role-playing, and abortive attempts. Symptoms may include talking about suicide, obtaining the means to commit suicide, withdrawing from social contacts, preoccupation with death, feeling trapped or hopeless about a situation, increased alcohol or drug use, engaging in risky or self-destructive behavior, and saying goodbye to people as if they will never see each other again.

[0276] Symptoms of depression include persistent anxious or sad feelings, helpless feelings, hopelessness, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, motor challenges, loss of interest in pleasurable activities or hobbies, poor concentration, low energy, low self-esteem, lack of positive thoughts or plans, excessive sleep, overeating, loss of appetite, insomnia, self-harm, thoughts of suicide and suicide attempts.The presence, severity, frequency and duration of symptoms may vary from case to case.Depression symptoms and their alleviation can be confirmed by a doctor or psychologist (for example, mental status examination). Anxiety disorders

[0277] Methods for treating anxiety disorders are provided herein. Anxiety disorders are an umbrella term that encompasses several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders.

[0278] Generalized anxiety disorder (GAD) is a common chronic disorder characterized by long-term anxiety that cannot be focused on any one object or situation. People suffering from GAD experience persistent, nonspecific fear and worry and become excessively worried about mundane events. GAD is the most common anxiety disorder affecting older adults.

[0279] In panic disorder, people suffer from brief attacks of intense fear and anxiety, often characterized by trembling, shaking, confusion, dizziness, nausea, and difficulty breathing. These panic attacks (defined by the APA as sudden onset of fear or discomfort that peaks in less than 10 minutes) can last for hours and can be triggered by stress, fear, or even exercise, although a specific cause is not always apparent. In addition to recurrent and unpredictable panic attacks, a diagnosis of phobic disorder also requires that the attacks have chronic consequences (either worry about the attack's potential meaning, persistent fear of future attacks, or significant changes in behavior related to the attack). Thus, patients with phobic disorder experience symptoms even outside of a specific panic episode. Often, normal changes in heart rate are noticed by the panic sufferer, leading them to believe that something is wrong with their heart or that they are experiencing another panic attack. In some cases, a heightened perception of bodily functions (hypervigilance) occurs during a panic attack, in which any perceived physiological change is interpreted as a possible life-threatening illness (i.e., excessive hypochondria).

[0280] Obsessive-compulsive disorder (OCD) is a type of anxiety disorder primarily characterized by recurrent obsessions (distressing, persistent, intrusive thoughts or images) and compulsions (urges to perform specific actions or rituals). OCD thought patterns can be linked to superstition, insofar as they involve the individual believing in nonexistent causal relationships. Often, the process is completely illogical. For example, a compulsion to walk in a particular pattern can be used to alleviate obsessive thoughts of impending danger. And in many cases, the compulsion is not entirely inexplicable but is simply a nervously triggered urge to complete a ritual. In a minority of cases, OCD patients may only experience obsessions without overt compulsions, and even fewer experience only compulsions.

[0281] One of the largest categories of anxiety disorders is that of phobias, which encompasses all cases in which fear and anxiety are triggered by a particular stimulus or situation. Patients typically anticipate frightening consequences from encountering the object of their fear (which could be anything from an animal to a place to a bodily fluid).

[0282] Post-traumatic stress disorder, or PTSD, is an anxiety disorder that results from a traumatic experience. Post-traumatic stress can result from extreme situations (e.g., war, rape, hostage situations, or even serious misfortune). It can also result from prolonged (chronic) exposure to severe stressors (e.g., soldiers who tolerate individual combat but do not cope well with continuous war). Common symptoms include flashbacks, avoidance behaviors, and depression. epilepsy

[0283] Epilepsy is a brain disorder characterized by repeated seizures over a long period of time. Types of epilepsy can include, but are not limited to, generalized epilepsy, such as childhood absence epilepsy, juvenile myoclonic epilepsy, epilepsy with awakening grand mal seizures, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, such as temporal lobe epilepsy, frontal lobe epilepsy, and benign focal epilepsy of childhood. Epilepsy

[0284] Epileptogenesis is the stepwise process by which a normal brain develops epilepsy, a chronic condition in which seizures occur. Epileptogenesis results from neuronal damage caused by an initial insult (e.g., status epilepticus). Status epilepticus (SE)

[0285] Status epilepticus (SE) can include, for example, convulsive status epilepticus, such as early status epilepticus, established status epilepticus, refractory status epilepticus, and very refractory status epilepticus; non-convulsive status epilepticus, such as generalized status epilepticus, complex partial status epilepticus, generalized periodic epileptic discharges, and periodic unilateral epileptic discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epilepticus and can include early status epilepticus, established status epilepticus, refractory status epilepticus, and very refractory status epilepticus. Early status epilepticus is treated with first-line therapy. Established status epilepticus is characterized by persistent status epilepticus despite treatment with first-line therapy and second-line therapy is administered. Refractory status epilepticus is characterized by persistent status epilepticus despite treatment with first-line and second-line therapy and general anesthetics are commonly administered. Super-refractory status epilepticus is characterized by persistent status epilepticus despite treatment with first-line therapy, second-line therapy, and general anesthetics for 24 hours or more.

[0286] Non-convulsive status epilepticus can include, for example, focal non-convulsive status epilepticus, e.g., complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, minimal non-convulsive status epilepticus; generalized non-convulsive status epilepticus, e.g., late-onset absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus. Seizures

[0287] A seizure is a physical finding or change in behavior that occurs after an episode of abnormal electrical activity in the brain. The term "seizure" is often used interchangeably with "convulsion." A convulsion is when a person's body shakes rapidly and uncontrollably. During a convulsion, the person's muscles repeatedly contract and relax.

[0288] Based on the type of behavior and brain activity, seizures are divided into two broad categories: generalized and partial (also called focal or localized). Classifying the type of seizure helps doctors diagnose whether a patient has epilepsy.

[0289] Generalized seizures are caused by electrical impulses from the entire brain, while partial seizures are caused (at least initially) by electrical impulses in a smaller part of the brain. The part of the brain that generates the seizure is sometimes called the focus.

[0290] There are six types of generalized seizures. The most common, dramatic, and therefore best known is a generalized convulsion (also called a grand mal seizure). In this type of seizure, the patient loses consciousness and usually collapses. This loss of consciousness is followed by 30-60 seconds of generalized rigidity (called the "tonic" phase of the seizure), followed by 30-60 seconds of violent spasms (the "clonic" phase), after which the patient falls into a deep sleep (the "postictal" or after-seizure phase). During a grand mal seizure, impairments and accidents (e.g., tongue biting and urinary incontinence) can occur.

[0291] Absence attacks cause a brief (only a few seconds) loss of consciousness with few or no symptoms. Patients (most often children) typically cease activity and These attacks start and end abruptly and can occur several times a day. Patients are usually unaware they are having an attack, except that they may notice they are "losing time."

[0292] Myoclonic seizures consist of sporadic jerks, usually on both sides of the body. Patients sometimes describe these jerks as brief electric shocks. When severe, these seizures can result in dropping or involuntary throwing of objects.

[0293] Clonic seizures are recurrent rhythmic spasms that involve both sides of the body simultaneously.

[0294] Tonic seizures are characterized by muscle stiffness.

[0295] Atonic seizures consist of a sudden loss of muscle tone throughout the body, especially the arms and legs, often resulting in a fall. Seizures described herein can include epileptic seizures; acute repetitive seizures; cluster seizures; continuous seizures; continuous seizures; persistent seizures; recurrent seizures; status epilepticus, e.g., refractory convulsive status epilepticus, non-convulsive status epilepticus; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondarily generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign rolandic seizures; febrile seizures; affective seizures; focal seizures; galactocele; generalized onset seizures; infantile spasms; Jackson seizures; generalized bilateral myoclonic seizures; multifocal seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post-traumatic seizures; petit mal seizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures. In some embodiments, the seizures are generalized seizures associated with Dravet syndrome, Lennox-Gestaurt syndrome, tuberous sclerosis complex, Rett syndrome, or PCDH19 female epilepsy. Abbreviation PCC: Pyridinium chlorochromate; t-BuOK: Potassium tert-butoxide; 9-BBN: 9-Borabicyclo[3.3.1]nonane; Pd(t-Bu3P)2: Bis(tri-tert-butylphosphine)palladium(0); AcCl: Acetyl chloride; i-PrMgCl: Isopropylmagnesium chloride; TBSCl: tert-butyl(chloro)dimethylsilane; (i-PrO)4Ti: Titanium tetraisopropoxide; BHT: 2,6-di-t-butyl-4-methylphenoxide; Me: Methyl; i-Pr: Iso -Propyl; t-Bu: tert-butyl; Ph: phenyl; Et: ethyl; Bz: benzoyl; BzCl: benzoyl chloride; CsF: cesium fluoride; DCC: dicyclohexylcarbodiimide; DCM: dichloromethane; DMAP: 4-dimethylaminopyridine; DMP: Dess-Martin periodinane; EtMgBr: ethyl magnesium bromide; EtOAc: ethyl acetate; TEA: triethylamine; AlaOH: alanine; Boc: t-butoxycarbonyl; Py: pyridine; TBAF: tetra-n-butylammonium fluoride; THF: tetrahydrofuran; TBS: t-butyldimethylsilyl; TMS: trimethylsilyl; TMSCF3: (trifluoromethyl)trimethylsilane; Ts: p-toluenesulfonyl; Bu: butyl; Ti(OiPr)4: tetraisopropoxytitanium; LAH: lithium aluminum hydride; LDA: lithium diisopropylamide; LiOH.H2O: lithium hydroxide hydrate; MAD: methylaluminum bis(2,6-di-t-butyl-4-methylphenoxide); MeCN: acetonitrile; NBS: N- Bromosuccinimide; Na2SO4: sodium sulfate; Na2S2O3: sodium thiosulfate; PE: petroleum ether; MeCN: acetonitrile; MeOH: methanol; Boc: t-butoxycarbonyl; MTBE: methyl tert-butyl ether; DMSO: dimethyl sulfoxide; DMF: N,N-dimethylformamide; 9-BBN: 9-borabicyclo[3.3.1]nonane; MePPh3Br: bromo(methyl)triphenylphosphorane; MeMgBr: methylmagnesium bromide; MeLi: methyllithium; Na HCO3: sodium bicarbonate. [Example]

[0296] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described herein are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and are not to be construed in any way as limiting the scope thereof.

[0297] Unless otherwise indicated, the stereochemistry assigned herein (e.g., the assignment of "R" or "S" to position C24 of a steroid) may be tentatively (e.g., randomly) assigned. For example, if the absolute configuration is "S," then position C24 may be depicted in the "R" configuration. If the absolute configuration is "R," then position C24 may be depicted in the "S" configuration.

[0298] The absolute configuration of an asymmetric center can be determined using methods known to those skilled in the art. In some embodiments, the absolute configuration of an asymmetric center in a compound can be elucidated from the X-ray single crystal structure of the compound. In some embodiments, the absolute configuration of an asymmetric center elucidated by the X-ray crystal structure of a compound can be used to infer the absolute configuration of a corresponding asymmetric center in another compound obtained from the same or similar synthetic methodology ... 1 H NMR spectroscopy or 19 In conjunction with F NMR spectroscopy, it can be used to deduce the absolute configuration of the corresponding asymmetric center in another compound. material and method

[0299] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, but it is understood that other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization.

[0300] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The selection of a suitable protecting group for a particular functional group and suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups and their introduction and removal are described in T.W. Greene and P.G.M. Buts, Protecting Groups in Organic Synthesis, 2nd Edition, Wiley, New York, 1991, and the references cited therein.

[0301] The compounds provided herein can be isolated and purified by known standard procedures. Such procedures include, but are not limited to, recrystallization, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following schemes are presented in detail for the preparation of representative oxysterols listed herein. The compounds provided herein can be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis. Exemplary chiral columns available for use in the separation / purification of enantiomers / diastereomers provided herein include, but are not limited to, CHIRALPAK® AD-10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ, and CHIRALCEL® OK. I can't.

[0302] (e.g., for the region between δ (ppm) of about 0.5 and about 4 ppm) 1 It should be understood that H-NMR is an exemplary interpretation of the NMR spectrum of a compound (e.g., exemplary peak integration). Exemplary general method for preparative HPLC: Column: Waters RBridge prep 10 μm C18, 19×250 mm. Mobile phase: acetonitrile, water (NH4HCO3) (30 L water, 24 g NH4HCO3, 30 mL NH3.H2O). Flow rate: 25 mL / min.

[0303] Exemplary general method for analytical HPLC: Mobile phase: A: water (10 mM NH4HCO3), B: acetonitrile. Gradient: 5% to 95% B in 1.6 or 2 min. Flow rate: 1.8 or 2 mL / min. Column: XBridge C18, 4.6 x 50 mm, 3.5 μm, 45°C.

[0304] An exemplary general method for SFC: Column: CHIRALPAK® AD CSP (250 mm * 30 mm, 10 μm), Gradient: 45% B, A = NH₃H₂O, B = MeOH, Flow rate: 60 mL / min. For example, AD_3_EtOH_DEA_5_40_25ML would indicate "Column: Chiralpak AD-3 150 x 4.6 mm ID, 3 μm, Mobile phase: A: CO₂ B: Ethanol (0.05% DEA) Gradient: 5% to 40% B in 5 min and hold at 40% for 2.5 min, then 5% B for 2.5 min. Flow rate: 2.5 mL / min. Column temperature: 35°C." Example 1: NMDA Potentiation NMDA potentiation Whole-cell patch clamp of mammalian cells (Ionworks Barracuda (IWB))

[0305] Whole-cell patch clamp techniques were used to investigate the effects of compounds on GlunN1 / GluN2A glutamate receptors expressed in mammalian cells.

[0306] HEK293 cells were transformed with adenovirus 5 DNA and transfected with cDNA encoding the human GRIN1 / GRIN2A gene. Stable transfectants were selected using G418 and Zeocin resistance genes incorporated into the expression plasmid, and selection pressure was maintained with G418 and Zeocin in the medium. Cells were cultured in Dulbecco's modified Eagle's medium / nutrient mixture (D-MEM / F-12) supplemented with 10% fetal bovine serum, 100 μg / ml penicillin G sodium, 100 μg / ml streptomycin sulfate, 100 μg / ml Zeocin, 5 μg / ml blasticidin, and 500 μg / ml G418.

[0307] The effects of test articles were evaluated in an 8-point concentration response format (quadruplicate wells / concentration). All test and control solutions contained 0.3% DMSO and 0.01% Kolliphor® EL (C5135, Sigma). Test article formulations were loaded into 384-well compound plates using an automated liquid handling system (SciClone ALH3000, Caliper LifeSciences). Measurements were performed using the IonWorks Barracuda platform according to the following procedure: Electrophysiological procedures:

[0308] Intracellular solution (mM): 50 mM CsCl, 90 mM CsF, 2 mM MgCl2, 5 mM EGTA, 10 mM HEPES. Adjust pH to 7.2 with CsOH.

[0309] Extracellular solution, HB-PS (composition in mM): NaCl, 137; KCl, 1.0; CaCl, 5; HEPES, 10; glucose, 10; pH adjusted to 7.4 with NaOH (refrigerated until use).

[0310] Holding potential: -70 mV, potential during agonist / PAM amplification: -40 mV. Recording Procedure:

[0311] The extracellular buffer is loaded into the PPC plate wells (11 μL per well). The cell suspension is pipetted into the wells of the PPC planar electrodes (9 μL per well).

[0312] The whole-cell recording configuration is established by patch perforation and membrane currents are recorded by an on-board patch clamp amplifier.

[0313] Two recordings (scans) are made: one during preamplification of the test article alone (preamplification duration - 5 minutes) and the second during preamplification of the test article and agonist (EC 20 L-glutamate and 30 μM glycine) to detect the positive modulatory effects of the test article.

[0314] Test article administration: The first preapplication consisted of the addition of 20 μL of a 2x concentrated test article solution, and the second of 20 μL of a 1x concentrated test article and agonist at 10 μL / s (total application time of 2 seconds). Example 2: NAM and PAM Whole-cell patch clamp of mammalian cells (Ionworks Barracuda (IWB)) Whole-cell patch clamp techniques were used to investigate the effects of the positive allosteric modulation activity of test compounds on GlunN1 / GluN2A and GluN2B glutamate receptors expressed in mammalian cells. HEK293 cells were transformed with adenovirus 5 DNA and transfected with cDNA encoding the human GRIN1 / GRIN2A gene. Stable transfectants were selected using G418 and Zeocin resistance genes incorporated into the expression plasmid, and selection pressure was maintained with G418 and Zeocin in the medium. Cells were cultured in Dulbecco's modified Eagle's medium / nutrient mixture (D-MEM / F-12) supplemented with 10% fetal bovine serum, 100 μg / ml penicillin G sodium, 100 μg / ml streptomycin sulfate, 100 μg / ml Zeocin, 5 μg / ml blasticidin, and 500 μg / ml G418. The effects of test articles were evaluated in an 8-point concentration response format (quadruplicate wells / concentration). All test and control solutions contained 0.3% DMSO and 0.01% Kolliphor® EL (C5135, Sigma). Test article formulations were loaded into 384-well compound plates using an automated liquid handling system (SciClone ALH3000, Caliper LifeSciences). Measurements were performed using the IonWorks Barracuda platform according to the following procedure: Electrophysiological procedures: a) Intracellular solution (mM): 50 mM CsCl, 90 mM CsF, 2 mM MgCl2, 5 mM EGTA, 10 mM HEPES. Adjust pH to 7.2 with CsOH. b) Extracellular solution, HB-PS (composition in mM): NaCl, 137; KCl, 1.0; CaCl2, 5; HEPES, 10; glucose, 10; pH adjusted to 7.4 with NaOH (refrigerated until use). c) Holding potential: -70 mV, potential during agonist / PAM amplification: -40 mV. Recording Procedure: a) Extracellular buffer is loaded into PPC plate wells (11 μL per well). Cell suspension is pipetted into the wells of the PPC planar electrodes (9 μL per well). b) The whole-cell recording configuration is established by patch perforation and membrane currents are recorded by an on-board patch clamp amplifier. c) Two recordings (scans) are made: one during pre-amplification of the test article alone (pre-amplification duration - 5 minutes) and the second during pre-amplification of the test article and agonist (EC 20 L-glutamate and 30 μM glycine) to detect the positive modulatory effects of the test article. Test article administration: The first preapplication consisted of the addition of 20 μL of a 2x concentrated test article solution, and the second of 20 μL of a 1x concentrated test article and agonist at 10 μL / s (total application time of 2 seconds). Synergistic effects of positive allosteric modulators (PAMs) on the channel The synergistic effect of a positive allosteric modulator (PAM) on the channel is calculated as follows: %activation=(I PAM / I EC10-30 )×100%-100% In the formula, I PAM is the L-glutamate EC50 in the presence of various concentrations of the test article. 10-30 is the induced current, and I EC20 L-glutamate EC 20 is the average current induced by The PAM concentration response data is fitted to an equation of the following form: %Activation = %L-Glutamate EC 20 +{(%MAX-%L-Glutamate EC 20 ) / [1+([Test] / EC 50 ) N ]} where [Test] is the concentration of PAM (test article) and EC 50 is the concentration of PAM that results in half-maximal activation, N is the Hill coefficient, and % L-glutamate EC 20 L-glutamate EC 20 %MAX is the percentage of current evoked by L-glutamate EC 20 % activation is the percentage of current activated by the highest dose of PAM co-administered with L-glutamate EC50 at each PAM concentration. 10-30 is the percentage of the current evoked by The maximum amplitude of the evoked current is measured and defined as the peak current amplitude (PCA). Automated patch-clamp system (QPatch HTX): In this study, HEK 293 cells stably transfected with glutamate-activated channels of the GRIN1 / 2A subtype are used together with a submaximal NMDA concentration (300 μM NMDA, co-applied with 8 μM glycine) to investigate the negative allosteric modulation of test compounds. cell culture Typically, cells are passaged at approximately 80%-90% confluence. For electrophysiological measurements, cells are harvested from sterile culture flasks containing complete culture medium at approximately 80%-90% confluence. The cells are suspended in PBS and transferred to a QPatch 16X or QPatch HTX system for centrifugation / washing. Standard laboratory conditions: cells are incubated at 37° C. in a humidified atmosphere containing 5% CO 2 (approximately 95% relative humidity). Culture medium: Cells are continuously maintained and passaged in sterile culture flasks containing a 1:1 mixture of Dulbecco's modified Eagle's medium and nutrient mixture F-12 (D-MEM / F-12 1x, liquid, with L-glutamine) supplemented with 10% fetal bovine serum, 1% penicillin / streptomycin solution, and 50 μM AP-5 blocker. Antibiotics: Supplement the complete medium indicated above with 100 μg / mL hygromycin, 15 μg / mL blasticidin and 1 μg / mL puromycin. Induction of expression: 24 hours before the start of the experiment, add 2.5 μg / mL tetracycline. Dosage Formulation Dose levels are converted to test compound as supplied. Vehicle is added to achieve a stock concentration of 10 mM (stored at -10°C to -30°C). An additional stock solution of 1.0 mM is prepared in DMSO. Details of stock solution utilization (thawing, dosage formulation) are recorded in the raw data. Time of stock solution utilization is detailed in the report. Test Compound Concentration Dose levels are converted to test compound as supplied. Vehicle is added to achieve a stock concentration of 10 mM (stored at -10°C to -30°C). An additional stock solution of 1.0 mM is prepared in DMSO. Details of stock solution utilization (thawing, dosage formulation) are recorded in the raw data. Time of stock solution utilization is detailed in the report. One test concentration of 1.0 μM is tested. Prepare all test solutions immediately before electrophysiological experiments by diluting stock solutions with either Mg-free bath solution alone or Mg-free bath solution containing NMDA (300 µM) and glycine (8.0 µM) and keep them at room temperature (19 °C-30 °C) when used. Use 0.1% DMSO as a vehicle. Preparation frequency: Prepare fresh solutions of test compounds daily for each test concentration. Stability of Dose Formulation: All preparation times are recorded in the raw data. Any observations regarding instability of the test compound are noted in the raw data. Storage of dosage formulation: On the day of the experiment, maintain the dosage formulation at room temperature (19°C to 30°C) until use. Bath solution In preparing the experiment and forming the giga-ohm-seal, the following standard bath solutions are used: Sodium chloride: 137 mM; potassium chloride: 4 mM; calcium chloride: 1.8 mM; magnesium chloride: 1 mM; HEPES: 10 mM; D-glucose: 10 mM; Cremophor: 0.02%; pH (NaOH): 7.4 Prepare 1x bath solution by diluting glucose-free 10x bath solution and 100x glucose solution with water at least every 7 days. Prepare both stock solutions before the start of the experiment and store them at 1°C to 9°C (10x bath solution) or -10°C to -30°C (100x glucose solution). Record the batch number of the bath solution used in the experiment in the raw data. When in use, keep 1x bath solution at room temperature (19°C to 30°C). When not in use, store 1x bath solution at 1°C to 9°C. After formation of the giga-seal, the following Mg-free bath solution is used: 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 This Mg-free bath solution is prepared as a 1× solution and stored at 1° C. to 9° C. Prepare it fresh at least every 10 days. Intracellular solution From the frozen 1x intracellular solution prepared prior to the start of the experiments in this study, 1x intracellular solution is thawed daily, aliquoted, and stored at -10°C to -30°C. When used, the 1x intracellular solution is kept at room temperature (19°C to 30°C). The remaining 1x intracellular solution is stored in the refrigerator (1°C to 9°C). The 1x intracellular solution contains the components outlined below: Potassium chloride: 130 mM; magnesium chloride: 1 mM; Mg-ATP: 5 mM; HEPES: 10 mM; EGTA: 5 mM; pH (KOH): 7.2 Cell treatment In this study, cells are continuously perfused with NMDA / glycine, test compound, or test compound / NMDA / glycine. In all cases, a pre-wash step of at least 30 seconds with test compound is performed between applications. See Table A below for details. At least n=3 isolated cells were analyzed for each experimental type. Prior to starting, prepare NMDA and glycine stock solutions and store frozen (-10°C to -30°C) until the day of the experiment. Immediately prior to the electrophysiological experiment, thaw and dilute the frozen stock solutions. Control: To ensure successful expression of NMDA receptors, measure the effects of vehicle (0.1% DMSO) and D-(-)-2-amino-5-phosphonopentanoic acid (AP-5) (100 μM) in triplicate cells every two weeks. Prior to the start of the experiments, a 50 mM stock solution of AP-5 was prepared, aliquoted, and stored frozen (-10 to -30°C) until the day of the experiment. Immediately prior to the electrophysiological experiments, the frozen stock solution was thawed and then diluted with Mg-free bath solution containing NMDA (300 μM) and glycine (8.0 μM) to obtain a final perfusion concentration of 100 μM. Experimental procedure Cells are transferred to the QPatch HTX system as a suspension in serum-free medium and maintained in a cell storage tank / stirrer throughout the experiment. All solutions applied to the cells, including the intracellular solution, are maintained at room temperature (19-30°C). The standard bath solution described above is used during the sealing process. All solutions applied to the cell, including the pipette solution, are maintained at room temperature (19-30°C). After formation of a gigaohm seal between the patch electrode and an individual transfected HEK293 cell, only Mg-free bath solution is perfused, and the cell membrane is ruptured to ensure electrical access to the cell interior (whole-cell patch configuration). 300 μM NMDA (and 8.0 μM glycine) is applied to the patch-clamped cell for 5 seconds to measure inward currents. Cells are voltage-clamped at a holding potential of -80 mV throughout the entire experiment. For test compound analysis, NMDA receptors are stimulated by the following combination of 300 μM NMDA and 8.0 μM glycine and test compound: A 30 second pre-wash step with test compound is performed between applications. [Table A] [Table B] Example 3. Synthesis of Compound 1. [ka]

[0315] Step 1. To a mixture of MePPhBr (1.28 kg, 3.6 mol) in THF (4.5 L) was added t-BuOK (404 g, 3.6 mol) under N at 15° C. The resulting mixture was stirred at 50° C. for 30 minutes. Pregnenolone (950 g, 2.9 mol) was added in portions below 65° C. The reaction mixture was stirred at 50° C. for 1 hour. The combined mixture The mixture was quenched with saturated aqueous NH4Cl (1 L) at 15 °C. The THF layer was separated. The aqueous phase was extracted with EtOAc (2 x 2 L). The combined organic phase was concentrated in vacuo to give a solid. This solid was further purified by trituration with MeOH / HO (1:1, 15 L) at reflux to give A-1 (940 g, 99%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 5.40-5.32 (m, 1H), 4.85 (s, 1H), 4.71 (s, 1H), 3.58-3.46 (m, 1H), 2.36-2.16 (m, 2H), 2.08-1.94 (m, 2H), 1.92-1.62 (m, 9H), 1.61-1.39 (m, 6H), 1.29-1.03 (m, 4H), 1.01 (s, 3H), 0.99-0.91 (m, 1H), 0.59 (s, 3H).

[0316] Step 2. To a solution of A-1 (800 g, 2.54 mol) in DCM (8 L) was added DMP (2.14 kg, 5.08 mol) portionwise at 35 °C. The reaction mixture was stirred at 35 °C for 20 min. The reaction mixture was filtered. The filter cake was washed with DCM (3 × 1 L). The combined organic phase was washed with saturated NaSO / saturated aqueous NaHCO (3:1, 2 × 1.5 L), brine (1.5 L), dried over NaSO, filtered, and concentrated in vacuo to give A-2 (794 g, crude) as a solid, which was used directly in the next step.

[0317] Step 3. To a solution of TBAF (3.04 mL, 1 M in THF, 3.04 mmol, Aldrich) in THF (100 mL) was added TMSCF (25.8 g, 182 mmol) followed by a solution of A-2 (19 g, 60.8 mmol) in THF (100 mL) dropwise at 0 °C. The mixture was stirred at 0 °C for 30 min. To the mixture was added TBAF (200 mL, 1 M in THF, 200 mmol) at 0 °C. The mixture was stirred at 0 °C for another 30 min. To the mixture was added saturated aqueous NH Cl (100 mL), and the mixture was concentrated in vacuo. To the residue was added PE / EtOAc (400 mL, 1:1), and the organic layer was separated and combined with two other batches (2 × 10 g of A-2). The combined organic layers were washed with water (300 mL), brine (300 mL), dried over NaSO, filtered, and concentrated in vacuo to give an oil. The residue was dissolved in DCM (150 mL) and diluted with PE (750 mL). The solution was poured onto a silica gel column (500 g, 100-200 mesh) and eluted with PE:DCM:EtOAc = 5:1:0.05 to 5:1:0.1 to give A-4 (12 g, 17% yield) as an oil and impure A-3. Impure A-3 was recrystallized from MeCN (250 mL) to give purified A-3 (6.5 g) as a solid. A-3 recovered from the MeCN filtrate was subjected to silica gel chromatography (PE:DCM:EtOAc = 50:1:1 to 20:1:1) to give the crude product, which was recrystallized from MeCN (20 mL) to give purified A-3 (1 g, 16% overall yield) as a solid. 3 JH,CF3 A-3 and A-4 were identified from (FDCS).(J.Org.Chem.2015,80,1754.). A-3: 1 H NMR (400 MHz, CDCl3) δ 5.43-5.33 (m, 1H), 4.85 (s, 1H), 4.71 (s, 1H); 2.49 (s, 2H); 2.11-1.97 (m, 4H), 1.95-1.32 (m, 14H), 1.30-0.98 (m, 7H), 0.59 (s, 3H). A-4: 1 H NMR (400 MHz, CDCl3) δ 5.54-5.41 (m, 1H), 4.86 (s, 1H), 4.72 (s, 1H); 2.78-2.65 (m, 1H); 2.18-1.97 (m, 3H), 1.95-1.35 (m, 16H), 1.32-0.98 (m, 7H), 0.59 (s, 3H).

[0318] Step 4. To a solution of A-3 (8 g, 20.9 mmol) in THF (80 mL) was added 9-BBN dimer (5.85 g, 24 mmol). The mixture was stirred at 40° C. for 1 hour. The mixture was cooled to 0° C. To the mixture were added EtOH (12 mL), NaOH (41.8 mL, 5 M, aq.), and H2O2 (20.9 mL, 10 M, aq.) dropwise. The mixture was stirred at 50° C. for 1 hour and then cooled. The mixture To the residue was added NaSO (100 mL, 25%, aqueous solution). The mixture was extracted with EtOAc (300 mL). The organic layer was separated and purified by silica gel column chromatography (PE: EtOAc = 10:1 to 5:1) to give A-5 (7.1 g, 85%) as a solid. 1H NMR (400 MHz, CDCl3) δ 5.42-5.32 (m, 1H), 3.64 (dd, J = 3.2, 10.4 Hz, 1H), 3.37 (dd, J = 6.8, 10.4 Hz, 1H), 2.49 (s, 2H), 2.32-1.92 (m, 4H), 1.92-1.70 (m, 4H), 1.70-1.29 (m, 8H), 1.29-0.91 (m, 11H), 0.71 (s, 3H).

[0319] Step 5. To a solution of A-5 (7.1 g, 17.7 mmol) in DCM (30 mL) and pyridine (21 mL) was added TsCl (6.74 g, 35.4 mmol). The mixture was stirred at 15° C. for 2 hours. Water (5 mL) was added to the mixture, and the mixture was stirred at 15° C. for 2 hours. The mixture was concentrated in vacuo. To the residue was added water (100 mL) and EtOAc (200 mL). The organic layer was separated and washed with HCl (100 mL, 0.1 M), water (100 mL), and brine (100 mL). The organic layer was dried over NaSO, filtered, and concentrated in vacuo to give A-6 (9.8 g, 100%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 5.48-5.29 (m, 1H), 3.97 (dd, J = 2.4, 9.2 Hz, 1H), 3.77 (dd, J = 6.4, 9.2 Hz, 1H), 2.48 (s, 2H), 2.45 (s, 3H), 2.10-1.88 (m, 5H), 1.82-1.35 (m, 9H), 1.30-0.82 (m, 12H), 0.64 (s, 3H).

[0320] Step 6. To a solution of A-6 (1.05 g, 1.89 mmol) in DMF (5 mL) was added KI (1.25 g, 7.56 mmol). The mixture was stirred at 50° C. for 1 h. To the mixture was added PhSO2Na (0.93 g, 5.67 mmol). The mixture was stirred at 50° C. for 2 h. To the mixture was added water (10 mL) and DCM (30 mL). The organic layer was separated, dried over Na2SO4, filtered, concentrated in vacuo, and triturated from PE / DCM (10 mL, 5:1) to give A-7 (600 mg, 61%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 7.98-7.87 (m, 2H), 7.70-7.52 (m, 3H), 5.39-5.31 (m, 1H), 3.14 (d, J = 14.0 Hz, 1H), 2.85 (dd, J = 9.6, 14.0 Hz, 1H), 2.48 (s, 2H), 2.20-1.88 (m, 5H), 1.88-1.68 (m, 4H), 1.60-1.33 (m, 5H), 1.30-0.82 (m, 12H), 0.66 (s, 3H).

[0321] Step 7. To a solution of i-PrNH (576 mg, 5.70 mmol) in THF (10 mL) was added n-BuLi (1.9 mL, 2.5 M in hexanes, 4.75 mmol) at −70° C. The mixture was warmed to 0° C. A solution of A-7 (1 g, 1.9 mmol) in THF (8 mL) was added at −70° C. The mixture was stirred at −70° C. for 1 h. To the mixture was added a solution of 2-isopropyloxirane (245 mg, 2.85 mmol) in THF (2 mL) at −70° C. The mixture was stirred at −70° C. for 1 h, warmed to 10° C., and stirred at 10° C. for 16 h. To the mixture was added NH4Cl (5 mL, saturated aqueous solution). The mixture was extracted with EtOAc (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give A-8 (1.2 g, crude) as an oil.

[0322] Step 8. To a solution of A-8 (1.2 g, 1.96 mmol) in MeOH (60 mL) was added NiBr (5 mg, 0.023 mmol), and Mg powder (3.79 g, 156 mmol) was added portionwise at 60 °C within 30 min. The mixture was stirred at 60 °C for 10 min. The mixture was poured into HCl (160 mL, 2 M) and extracted with PE / EtOAc (2 × 200 mL, 1:1). The combined organic layers were washed with brine (100 mL), dried over Na SO , filtered, concentrated in vacuo, and purified by silica gel column (1 The crude product was purified twice by silica gel column (200-300 mesh, PE:DCM:acetone = 1:1:0.01) and recrystallized from MeCN / water (3:1, 5 mL) to give compound 1 (50 mg, 5%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 5.41-5.32 (m, 1H), 3.39-3.28 (m, 1H), 2.49 (s, 2H), 2.10-1.92 (m, 4H), 1.90-1.60 (m, 5H), 1.55-1.33 (m, 8H), 1.31-1.10 (m, 6H), 1.09-0.90 (m, 15H), 0.68 (s, 3H). LCMS Rt=1.278 min (2.0 min chromatography), 30-90AB, C 28 H 44 FO[M+H-HO] + MS ESI calculated value 453, measured value 453. Example 4. Synthesis of compounds 1-A and 1-B. [ka]

[0323] Step 1. To a solution of compound 1 (100 mg, 0.212 mmol) in pyridine (3 mL) was added benzoyl chloride (59.7 mg, 0.425 mmol) at 25 °C. The reaction was stirred at 25 °C for 16 hours. The reaction was quenched with water (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column (PE / EtOAc = 10 / 1) to give the desired product A-9 (150 mg, crude) as a solid. LCMS Rt=1.544 min (2 min chromatography), 30-90AB, C 35 H 49 MS ESI calculated value of F3O3[M+Na]+: 597, found value: 597.

[0324] Step 2. A-9 (580 mg, 1.00 mmol) was purified by SFC separation (Column: AD (250 mm * 30 mm, 5 um), Gradient: 45% B (A = NH3HO, B = MeOH), Flow rate: 60 mL / min) to give A-10-A (200 mg, 34%, 95.5% deSFC (Column: Chiralpak AD-3 100 x 4.6 mm ID, 3 um, Mobile phase: A: CO2 B: iso-propanol (0.05% DEA), Gradient: 5% to 40% B for 4.5 min and hold at 40% for 2.5 min, then 5% B for 1 min, Flow rate: 2.8 mL / min, Column temperature: 40 °C)) as a solid, and A-10-B (215 mg, 37%, 99.5% deSFC (Column: Chiralpak AD-3 100×4.6mm ID, 3um, Mobile phase: A: CO2, B: iso-propanol (0.05% DEA),

[0325] Gradient: 5% to 40% B for 4.5 min and hold at 40% for 2.5 min, then 5% B for 1 min. Flow rate: 2.8 mL / min. Column temperature: 40°C)) was obtained as a solid. A-10-A: 1H NMR (400MHz, CDCl3) δ 8.07-8.02 (m, 2H), 7.58-7.52 (m, 1H), 7.48-7.41 (m, 2H), 5.37-5.35 (m, 1H), 4.99-4.94 (m, 1H), 2.48-2.46 (m, 2H), 2.04-1.89 (m, 4H), 1.82-1.65 (m, 5H), 1.51-1.35 (m, 7H), 1.27-1.08 (m, 4H), 1.05 (s, 4H), 1.02-0.92 (m, 13H), 0.64 (s, 3H). A-10-B: 1 H NMR (400MHz, CDCl3) δ 8.07-8.02 (m, 2H), 7.59-7.52 (m, 1H), 7.49-7.40 (m, 2H), 5.37-5.35 (m, 1H), 5.01-4.92 (m, 1H), 2.48-2.46 (m, 2H), 2.03-1.90 (m, 5H), 1.83-1.66 (m, 3H), 1.83-1.66 (m, 1H), 1.51-1.37 (m, 8H), 1.23-1.11 (m, 3H), 1.05-1.00 (m, 5H), 0.99 - 0.90 (m, 12H), 0.66 (s, 3H).

[0326] Step 2a. To a solution of A-10-A (215 mg, 0.374 mmol) in THF (2 mL) and MeOH (2 mL) was added NaOH (400 mg, 10 mmol) and HO (2 mL) at 25 °C. The solution was stirred at 50 °C for 48 h. The reaction solution was extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo to give the crude product, which was triturated with MeCN (2 × 5 mL) to give the desired product, compound 1-A (148 mg, 84%), as a solid. Compound 1-A: 1H NMR (400MHz, CDCl3) δ 5.38-5.36 (m, 1H), 3.33-3.31 (m, 1H), 2.49-2.48 (m, 2H), 2.08-1.92 (m, 4H), 1.89-1.61 (m, 5H), 1.52-1.37 (m, 5H), 1.32-1.09 (m, 7H), 1.06-0.96 (m, 7H), 0.96-0.87 (m, 10H), 0.68 (s, 3H). LCMS Rt=1.497 min (2 min chromatography), 30-90AB, C 28 H 44 MS ESI calculated for F3O[M+H-H2O]+: 453, found: 453.

[0327] Step 2b. To a solution of A-10-B (200 mg, 0.348 mmol) in THF (2 mL) and MeOH (2 mL) was added NaOH (400 mg, 10 mmol) and HO (2 mL) at 25 °C. The solution was stirred at 50 °C for 48 h. The reaction solution was extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo to give the crude product, which was triturated with MeCN (2 × 5 mL) to give the desired product, compound 1-B (139 mg, 85%) as a solid. Compound 1-B: 1 H NMR (400MHz, CDCl3) δ 5.38-5.36 (m, 1H), 3.33-3.31 (m, 1H), 2.49-2.48 (m, 2H), 2.12-1.92 (m, 5H), 1.89-1.40 (m, 12H), 1.29-1.11 (m, 5H), 1.09-0.98 (m, 6H), 0.95-0.89 (m, 10H), 0.69 (s, 3H) LCMS Rt=1.500 min (2 min chromatography), 30-90AB, C 28 H 44 FO[M+H-HO] + MS ESI calculated value 453, measured value 453.

[0328] Synthesis of Compound 1-A - Absolute Stereochemistry [ka]

[0329] The experimental procedure for intermediate ST-200-CF3_4A or A-7 can be found in Example 3.

[0330] Synthesis of ST-200-096-004_1 [ka] To a solution of ST-200-096-004_1 (450 mg, 0.736 mmol) in methanol (30 mL) was added Mg powder (883 mg, 36.8 mmol) at 65 °C under N2. The reaction mixture was quenched dropwise with HCl (50 mL) until the solution became clear. The reaction solution was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with saturated NaHCO3 (50 mL), brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column (0–12% EtOAc in PE) to give ST-200-096-004_2 (150 mg, 43%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 5.40-5.34 (m, 1H), 3.37-3.25 (m, 1H), 2.55-2.40 (m, 2H), 2.09-1.91 (m, 4H), 1.90-1.70 (m, 3H), 1.69-1.56 (m, 4H), 1.54-1.35 (m, 6H), 1.34-0.97 (m, 12H), 0.96-0.86 (m, 9H), 0.68 (s, 3H).

[0331] Synthesis of ST-200-096-004_3 [ka] ST-200-096-004_2 (150 mg, 0.318 mmol) pyridine ( To a solution of 134 mg (0.954 mmol) of BzCl in 3 mL of HCl was added at 0° C., and the reaction was stirred at 25° C. for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×40 mL). The organic layer was washed with brine (5×50 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column (PE / EtOAc = 10 / 1 to 4 / 1) to give ST-200-096-004_3 (120 mg, 66%) as a solid. ST-200-096-004_3 (120 mg, 0.208 mmol) was separated by SFC (column: AD (250 mm * 30 mm, 5 um)), gradient: 25-25% B (0.1% NH3HO IPA)) to give ST-200-096-004_4 (100 mg, 84%) as a solid. 1 HNMR (400 MHz, CDCl3) δ 8.05 (d, J = 8Hz, 2H), 7.55 (t, J = 8Hz, 1H), 7.44 (t, J = 8Hz, 2H), 5.38-5.34 (m, 1H), 4.98-4.91 (m, 1H), 2.48 (s, 2H), 2.09-1.89 (m, 4H), 1.86-1.67 (m, 4H), 1.53-1.34 (m, 10H), 1.17-1.00 (m, 7H), 0.99-0.91 (m, 12H), 0.64 (s, 3H). SFC Rt=3.473 min (10 min chromatography), AD_IPA(DEA)_5_40_2, 8ML_8MIN, 100%de.

[0332] Synthesis of compound 1-A [ka] To a solution of ST-200-096-004_4 (100 mg, 0.173 mmol) in THF (2 mL), MeOH (1 mL), and water (1 mL) was added KOH (48.5 mg, 0.865 mmol). The mixture was stirred at 60 °C for 16 h. The mixture was poured into water (20 mL) and extracted with EtOAc (2 × 40 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (PE / EtOAc = 5 / 1 to 3 / 1) to give compound 1-A (48 mg, 59%) as a solid. 1 HNMR (400 MHz, CDCl3) δ 5.40-5.35 (m, 1H), 3.35-3.28 (m, 1H), 2.49 (m, 2H), 2.09-1.93 (m, 4H), 1.89-1.59 (m, 6H), 1.54-1.22 (m, 10H), 1.20-0.97 (m, 9H), 0.95-0.89 (m, 9H), 0.68 (s, 3H). LCMS Rt=1.265 min (2.0 min chromatography), 30-90AB, 100% purity, C 28 H 44 MS ESI calculated for FO [M-HO + H] = 453, found 453. Example 5. Synthesis of compounds 2, 2-A, and 2-B. [ka]

[0333] Step 1. To a solution of pregnenolone (50 g, 157 mmol) in THF (750 mL) and MeOH (500 mL) was added Pd / C (20 g, 10%, dry). The mixture was stirred under H (25 psi) at 25 °C for 72 h. The mixture was filtered. The filtrate was concentrated in vacuo to give B-1 (47 g, 94%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 3.69-3.51 (m, 1H), 2.51 (t, J = 8.8 Hz, 1H), 2.21-2.12 (m, 1H), 2.11 (s, 3H), 2.05-1.98 (m, 1H), 1.88-1.77 (m, 1H), 1.77-1.53 ​​(m, 6H), 1.48-1.08 (m, 11H), 1.05-0.85 (m, 2H), 0.80 (s, 3H), 0.73-0.63 (m, 1H), 0.60 (s, 3H).

[0334] Step 2. To a suspension of MePPhBr (78.5 g, 220 mmol) in THF (250 mL) was added t-BuOK (24.6 g, 220 mmol). The mixture was stirred at 50° C. for 1 h. To this mixture was added B-1 (47 g, 147 mmol). The mixture was stirred at 50° C. for 1 h. To this mixture was added water (100 mL) and EA (500 mL). The organic layer was separated and concentrated in vacuo to give the crude product, which was triturated from MeOH / water (1000 mL, 1:1) at 50° C. After cooling, the mixture was filtered, and the solid was washed with MeOH / water (2×500 mL, 1:1) and dried in vacuo to give B-2 (45 g, 97%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 4.84 (s, 1H), 4.70 (s, 1H), 3.69-3.51 (m, 1H), 2.08-1.98 (m, 1H), 1.88-1.62 (m, 10H), 1.61-1.50 (m, 2H), 1.48-0.85 (m, 13H), 0.81 (s, 3H), 0.70-0.60 (m, 1H), 0.56 (s, 3H).

[0335] Step 3. To a solution of B-2 (45 g, 142 mmol) in DCM (500 mL) was added silica gel (90 g) and PCC (45.7 g, 213 mmol). The mixture was stirred at 20 °C for 3 h. To the mixture was added PE (500 mL). The mixture was filtered through a silica gel pad, and the solid was washed with PE / DCM (1:1, 2 L). The combined filtrate was concentrated to give B-3 (44 g, 98%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 4.85 (s, 1H), 4.71 (s, 1H), 2.48-2.20 (m , 3H), 2.12-1.98 (m, 3H), 1.90-1.49 (m, 10H), 1.47-1.08 (m, 8H), 1.01 (s, 3H), 0.99-0.71 (m, 2H), 0.58 (s, 3H). Step 4. To a solution of B-3 (20 g, 63.5 mmol) in THF (300 mL) was added CsF (19.2 g, 127 mmol). To this mixture was added TMSCF (18.0 g, 127 mmol) dropwise at 10 °C. The mixture was stirred at 10 °C for 2 hours. To this mixture was added TBAF (127 mL, 1 M in THF, 127 mmol) at 10 °C. The mixture was stirred at 20 °C for 3 hours. To this mixture was added water (200 mL). The mixture was concentrated in vacuo to remove THF. To the residue was added EtOAc (300 mL). The organic layer was separated and washed with water (100 mL), brine (100 mL), dried over Na2SO4, filtered, concentrated in vacuo, triturated from PE:DCM (500 mL, 20:1), and recrystallized from MeCN (200 mL) to give B-4 (7.1 g) as a solid. The filtrates from trituration and recrystallization were combined, concentrated in vacuo, and purified twice by silica gel column (PE:EtOAc = 30:1 to 10:1) to give impure B-4, which was recrystallized from MeCN (200 mL) to give B-4 (7.6 g, 60% overall yield) as a solid. 1 H NMR (400 MHz, CDCl3) δ 4.84 (s, 1H), 4.70 (s, 1H), 2.11-1.98 (m, 3H), 1.88-1.47 (m, 13H), 1.45-1.05 (m, 9H), 1.00-0.89 (m, 1H), 0.85 (s, 3H), 0.78-0.68 (m, 1H), 0.56 (s, 3H).

[0336] Step 5. To a solution of B-4 (14.7 g, 38.2 mmol) in THF (150 mL) was added 9-BBN dimer (10.7 g, 43.9 mmol). The mixture was stirred at 40 °C for 1 h. The mixture was cooled to 0 °C. EtOH (21.8 mL), NaOH (76.3 mL, 5 M, aq.), and HO (38.1 mL, 10 M, aq.) were added dropwise to the mixture. The mixture was stirred at 50 °C for 1 h. After cooling, NaSO (200 mL, 25%, aq.) was added to the mixture. The mixture was extracted with EtOAc (500 mL). The organic layer was separated, concentrated in vacuo, and triturated from water (400 mL) to give B-5 (15 g, 98%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 3.68-3.58 (m, 1H), 3.40-3.30 (m, 1H), 2.11-1.91 (m, 2H), 1.89-1.72 (m, 2H), 1.70-1.45 (m, 8H), 1.42-1.06 (m, 11H), 1.03 (d, J = 6.4 Hz, 3H), 1.00-0.88 (m, 2H), 0.85 (s, 3H), 0.75-0.68 (m, 1H), 0.67 (s, 3H).

[0337] Step 6. To a solution of B-5 (15 g, 17.7 mmol) in DCM (60 mL) and pyridine (42 mL) was added TsCl (14.1 g, 74.4 mmol). The mixture was stirred at 15° C. for 2 hours. Water (2 mL) was added to the mixture, and the mixture was stirred at 15° C. for 16 hours. Water (100 mL) was added to the mixture. The mixture was extracted with PE / EtOAc (2:1, 300 mL). The organic layer was separated, washed with HCl (200 mL, 1 M), water (100 mL), brine (100 mL), dried over NaSO, filtered, and concentrated in vacuo to give B-6 (23 g, crude) as a solid. 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 3.96 (dd, J = 3.2, 9.2 Hz, 1H), 3.76 (dd, J = 6.8, 9.2 Hz, 1H), 2.45 (s, 3H), 2.10-1.98 (m, 1H), 1.92-1.78 (m, 2H), 1.71-1.30 (m, 11H), 1.30-0.88 (m, 13H), 0.83 (s, 3H), 0.72-0.62 (m, 1H), 0.61 (s, 3H).

[0338] Step 7. To a solution of B-6 (23 g, 41.3 mmol) in DMF (100 mL) was added KI (27.3 g, 165 mmol). The mixture was stirred at 50° C. for 1 hour. To this mixture was added PhSO2Na (20.1 g, 123 mmol). The mixture was stirred at 50° C. for 16 hours. To this mixture was added DCM (200 mL), water (400 mL), and PE (2:1, 400 mL) with stirring. The organic layer was separated and washed with water (100 mL). The mixture was filtered, washed with PE (100 mL), brine (100 mL), dried over NaSO, filtered, and concentrated in vacuo to 150 mL, and a solid formed. The mixture was filtered, washed with PE (100 mL), and dried in vacuo to give B-7 (12 g, 55%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 7.95-7.88 (m, 2H), 7.70-7.61 (m, 1H), 7.60-7.51 (m, 2H), 3.13 (d, J = 13.2 Hz, 1H), 2.84 (dd, J = 9.2, 14.0 Hz, 1H), 2.20-1.89 (m, 4H), 1.88-1.44 (m, 8H), 1.43-0.88 (m, 15H), 0.83 (s, 3H), 0.72-0.65 (m, 1H), 0.63 (s, 3H).

[0339] Step 8. To a solution of i-PrNH (573 mg, 5.67 mmol) in THF (10 mL) was added BuLi (1.88 mL, 2.5 M in hexanes, 4.72 mmol) at −70° C. The mixture was warmed to 0° C. A solution of B-7 (1 g, 1.89 mmol) in THF (8 mL) was added at −70° C. The mixture was stirred at −70° C. for 1 h. To the mixture was added a solution of 2-isopropyloxirane (243 mg, 2.83 mmol) in THF (2 mL) at −70° C. The mixture was stirred at −70° C. for 1 h, at 10° C. for 16 h, and at 50° C. for 2 h. To the mixture was added NH4Cl (5 mL, saturated aqueous solution). The mixture was extracted with EtOAc (50 mL). The organic layer was dried over Na2SO4, filtered, concentrated in vacuo, and purified by silica gel column (PE: EtOAc = 12:1 to 8:1) to give B-8 (0.5 g, 43%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 7.95-7.85 (m, 2H), 7.70-7.52 (m, 3H), 3.63-3.46 (m, 1H), 3.44-3.31 (m, 1H), 2.18-1.61 (m, 8H), 1.55-1.11 (m, 13H), 1.11-0.78 (m, 18H), 0.72-0.60 (m, 2H), 0.50-0.40 (m, 3H).

[0340] Step 9. To a solution of B-8 (0.5 g, 0.815 mmol) in MeOH (50 mL) was added NiBr (2 mg, 0.009 mmol). Then, magnesium powder (2.22 g, 91.4 mmol) was added portionwise within 30 min at 60 °C. The mixture was stirred at 60 °C for 1 h. The mixture was poured into citric acid (200 mL, 10% aqueous solution) and extracted with PE / EtOAc (2 × 200 mL, 1:1). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na SO , filtered, concentrated in vacuo, and purified by silica gel column (PE: EtOAc = 20:1 to 10:1) to give compound 2 (290 mg, 67%) as a solid. 1H NMR (400 MHz, CDCl3) δ 3.37-3.28 (m, 1H), 2.12-2.01 (m, 1H), 2.00-1.91 (m, 2H), 1.87-1.77 (m, 2H), 1.71-1.58 (m, 5H), 1.50-1.00 (m, 19H), 0.96-0.88 (m, 10H), 0.85 (s, 3H), 0.72-0.67 (m, 1H), 0.67-0.64 (m, 3H). LCMS Rt=1.340 min (2.0 min chromatography), 30-90AB, no MS signal. 28 H 46 FO[M+H-HO] + HRMS ESI calculated value 455.3495, measured value 455.3489.

[0341] Step 10. Compound 2 (264 mg) was separated twice on a silica gel column (300-400 mesh, 30 × 250 mm, PE: EtOAc = 30: 1 to 15: 1) to give both compound 2-A (56 mg, 21%) and compound 2-B (101 mg, 38%) as solids.

[0342] The diastereomeric ratio of 2-A and 2-B was assessed by conversion of the alcohol to the benzoate ester: To a solution of compound 2-B (8 mg, 0.017 mmol) in DCM (0.5 mL) was added pyridine (132 mg, 1.68 mmol) and BzCl (23.7 mg, 0.169 mmol). The mixture was stirred at 25 °C for 20 min. To the mixture was added PE (5 mL). The mixture was washed with NaHCO (2 mL, saturated aqueous solution), HCl (2 mL, 1 M, aqueous solution), NaHCO (2 mL, saturated aqueous solution), and the resulting mixture was collected as a preparative TLC. Purification by LC (PE:DCM = 1:1) gave 2-B-Bz for SFC analysis (98.7% DE (Column: Chiralpak AD-3 150 x 4.6 mm ID, 3 μm; Mobile phase: A:CO2, B:isopropanol (0.05% DEA); Gradient: 5% to 40% B in 5 min, hold at 40% for 2.5 min, then 5% B in 2.5 min; Flow rate: 2.5 mL / min; Column temperature: 35 °C)).

[0343] To a solution of compound 2-A (3 mg, 0.006 mmol) in DCM (0.5 mL) was added pyridine (50 mg, 0.633 mmol) and BzCl (8.9 mg, 0.063 mmol). The mixture was stirred at 25° C. for 20 minutes. PE (5 mL) was added to the mixture. The mixture was washed with NaHCO3 (2 mL, saturated aqueous solution), HCl (2 mL, 1 M, aqueous solution), NaHCO3 (2 mL, saturated aqueous solution), and purified by preparative TLC (PE:DCM = 1:1) to give 2-A-Bz for SFC analysis (95.0% de (Column: Chiralpak AD-3 150 × 4.6 mm ID, 3 μm, Mobile phase: A:CO2 B:isopropanol (0.05% DEA), Gradient: 5% to 40% B in 5 min and hold at 40% for 2.5 min, then 5% B in 2.5 min, Flow rate: 2.5 mL / min, Column temperature: 35 °C)). Compound 2-A: 1 H NMR (400 MHz, CDCl3) δ 3.37-3.28 (m, 1H), 2.12-2.01 (m, 1H), 2.00-1.91 (m, 2H), 1.87-1.77 (m, 2H), 1.71-1.58 (m, 5H), 1.50-1.00 (m, 19H), 0.96-0.88 (m, 10H), 0.85 (s, 3H), 0.72-0.67 (m, 1H), 0.65 (s, 3H). LCMS Rt=1.329 min (2.0 min chromatography), 30-90AB, C 28 H 46 FO[M+H-HO] + MS ESI calculated value 455, found value 455. Compound 2-B: 1 H NMR (400 MHz, CDCl3) δ 3.37-3.28 (m, 1H), 2.12-2.01 (m, 1H), 2.00-1.91 (m, 2H), 1.87-1.77 (m, 2H), 1.71-1.58 (m, 4H), 1.50-1.30 (m, 10H), 1.30-1.00 (m, 10H), 0.96-0.88 (m, 10H), 0.85 (s, 3H), 0.72-0.67 (m, 1H), 0.66 (s, 3H). LCMS Rt=1.333 min (2.0 min chromatography), 30-90AB, C 28 H 46 FO[M+H-HO] + MS ESI calculated value 455, found value 455.

[0344] Synthesis of Compound 2-A - Absolute Stereochemistry [ka]

[0345] The experimental procedure for intermediate ST-200-CF3_6C can be found in Example 5.

[0346] Synthesis of ST-200-096-001_1 [ka] To THF (1 mL) was added n-BuLi (0.948 mL, 2.5 M in hexane, 2.37 mmol), followed by the addition of a solution of ST-200-CF3_6C (500 mg, 0.949 mmol) in THF (4 mL) at −70 °C. After stirring at −70 °C for 30 min, (2R)-2-(propan-2-yl)oxirane (122 mg, 1.42 mmol) was added at −70 °C. The mixture was gradually warmed to 25 °C and stirred at 25 °C for 16 h. The mixture was quenched with saturated NH4Cl (15 mL) and extracted with EtOAc (3 × 10 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated to give ST-200-096-001_1 (560 mg, crude) as an oil, which was used directly in the next step.

[0347] Synthesis of ST-200-096-001_2 [ka] To a solution of ST-200-096-001_1 (560 mg, 0.913 mmol) in methanol (30 mL) was added Mg powder (1.09 g, 45.6 mmol) at 65 °C under N2. The reaction mixture was quenched dropwise with HCl (60 mL) until the solution became clear. The reaction solution was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with saturated NaHCO3 (50 mL), brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column (0–12% EtOAc in PE) to give ST-200-096-001_2 (150 mg, 46%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 3.35-3.26 (m, 1H), 2.10-1.91 (m, 3H), 1.88-1.76 (m, 2H), 1.71-1.62 (m, 4H), 1.52-1.35 (m, 6H), 1.32-1.20 (m, 7H), 1.17-0.98 (m, 6H), 0.95-0.87 (m, 10H), 0.86-0.80 (m, 4H), 0.72-0.61 (m, 4H).

[0348] Synthesis of ST-200-096-001_3 [ka] To a solution of ST-200-096-001_2 (200 mg, 0.423 mmol) in pyridine (3 mL) was added BzCl (177 mg, 1.26 mmol) at 0 °C, and the reaction was stirred at 25 °C for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 × 40 mL). The organic layer was washed with brine (5 × 50 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column (PE / EtOAc = 10 / 1 to 4 / 1) to give ST-200-096-001_3 (150 mg, 62%) as an oil. ST-200-096-001_3 (150 mg, 0.26 mmol) was separated by SFC (column: AD (250 mm * 30 mm, 5 um)), gradient: 30-30% B (A = 0.1% NH3HO IPA)) to give ST-200-096-001_3 (120 mg, 81%) as a solid. 1 HNMR (400 MHz, CDCl3) δ 8.05 (d, J = 8Hz, 2H), 7.55 (t, J = 8Hz, 1H), 7.44 (t, J = 8Hz, 2H), 4.98-4.91 (m, 1H), 2.09-1.89 (m, 4H), 1.86-1.61 (m, 6H), 1.53-1.34 (m, 8H), 1.27-1.03 (m, 8H), 0.99-0.95 (m, 8H), 0.92-0.83 (m, 7H), 0.71-0.61 (m, 4H). SFC Rt=4.117 min (10 min chromatography), AD_3_IPA_EtOH_5_40_25ML, 99%de.

[0349] Synthesis of compound 2-A [ka] To a solution of ST-200-096-001_3 (120 mg, 0.208 mmol) in THF (2 mL), MeOH (1 mL), and water (1 mL) was added KOH (57.7 mg, 1.03 mmol). The mixture was stirred at 60 °C for 16 h, poured into water (20 mL), and extracted with EtOAc (2 × 40 mL). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (PE / EtOAc = 5 / 1 to 3 / 1) to give compound 2-A (82 mg, 83%) as a solid. 1 HNMR (400 MHz, CDCl3) δ 3.34-3.28 (m, 1H), 2.10-1.92 (m, 3H), 1.88-1.75 (m, 2H), 1.71-1.60 (m, 5H), 1.54-1.34 (m, 7H), 1.32-0.98 (m, 12H), 0.93-0.87 (m, 10H), 0.85 (s, 3H), 0.74-0.68 (m, 1H), 0.65 (s, 3H). MS C 28 H 47 F3O2Na[M+Na + ] MS ESI calculated value = 495, found value 495. Example 6. Synthesis of Compound 3. [ka]

[0350] Step 1. To a solution of n-BuLi (568 μL, 2.5 M in hexanes, 1.42 mmol) in THF (0.5 mL) was added dropwise a suspension of B-7 (300 mg, 0.5695 mmol) in THF (2.5 mL) at −65° C. under N. The mixture was stirred at −65° C. for 30 min. 2-(tert-butyl)oxirane (68.4 mg, 0.6834 mmol) was added dropwise at −65° C. The mixture was stirred for an additional 30 min and then gradually warmed to 25° C. and stirred at 25° C. for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl (30 mL) and extracted with ethyl acetate (3×20 mL). The combined organic phase was washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to give C-1 (380 mg, crude) as a solid, which was used directly in the next step.

[0351] Step 2. To a solution of C-1 (380 mg, 0.6062 mmol) and NiCl (7.81 mg, 0.06062 mmol) in dry methanol (20 mL) was added Mg powder (580 mg, 24.2 mmol) in four portions with stirring under N at 50 °C. The reaction mixture was stirred at 60 °C for 1 h. The reaction mixture was cooled and poured into ethyl acetate (150 mL). The mixture was washed with 1 M HCl (3 × 200 mL), saturated aqueous NaHCO (200 mL), brine (200 mL), dried over NaSO, filtered, and concentrated in vacuo to give a solid, which was purified by silica gel chromatography (PE: EtOAc = 8:1) to give impure compound 3 (310 mg) as a solid, which was purified by trituration with PE / DCM (15 mL / 1 mL) to give compound 3 (46 mg, 15%) as a solid. 1H NMR (400 MHz, CDCl3) δ 3.16-3.05 (m, 1H), 2.09-2.01 (m, 1H), 2.01-1.92 (m, 2H), 1.89-1.76 (m, 2H), 1.73-1.60 (m, 3H), 1.52-1.33 (m, 8H), 1.32-0.93 (m, 12H), 0.93-0.87 (m, 12H), 0.85 (s, 4H), 0.73-0.61 (m, 4H). 19 F NMR (400 MHz, CDCl3) δ 78.66. LCMS Rt=1.354 min (2 min chromatography), 30-90AB, C 29 H 48 FO[M-HO+H] + MS ESI calculated value 469, observed value 469. Example 7. Synthesis of Compound 4. [ka]

[0352] Step 1. To a solution of diisopropylamine (0.2 mL) in THF (0.2 mL) was added butyllithium (0.57 mL, 2.5 M in n-hexane) at −70° C. The mixture was warmed to 25° C. and stirred at 25° C. for 30 minutes. The mixture was cooled to −70° C., and a solution of B-7 (250 mg, 16.5 mmol) in THF (3 mL) was added. After stirring at −70° C. for 1 hour, (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropyl 4-methylbenzenesulfonate (see Example 30) (169 mg, 0.57 mmol) was added at −70° C. The mixture was warmed to 25° C. and stirred at this temperature for 16 hours. The mixture was quenched with saturated aqueous NH4Cl (5 mL). The mixture was extracted with EtOAc (2×8 mL), washed with brine (2×20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give crude product D-1 (300 mg, crude) as an oil, which was used directly in the next step.

[0353] Step 2. To a solution of D-1 (300 mg, crude) in MeOH (15 mL) was added Mg powder (549 mg, 22.9 mmol) and NiCl (5 mg) at 60 °C. The mixture was stirred at 60 °C for 1 h. EtOAc (20 mL) and aqueous HCl (30 mL) were added. The mixture was extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with water (3 × 50 mL), saturated NaHCO (2 × 50 mL), and brine (2 × 50 mL) to give the crude product, which was purified by flash column chromatography (0–30% EtOAc in PE) to give compound 4 (100 mg, impure), which was triturated with CHCN (5 mL) at 25 °C to give compound 4 (50 mg, 50%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 2.10-1.90 (m, 3H), 1.85-1.75 (m, 3H), 1.70-1.60 (m, 5H), 1.50-1.30 (m, 6H), 1.25-1.00 (m, 14H), 0.90-0.80 (m, 7H), 0.70-0.55 (m, 4H). LCMS Rt=1.264 min (2 min chromatography), 30-90AB, C 27 H 41 FO[M+H-HO] + MS ESI calculated value 495, found value 495. Example 8. Synthesis of compound E-1. [ka]

[0354] Step 1. To a solution of S,S-cat (2 g, 3.65 mmol) in anhydrous DCM (30 mL) was added a solution of cobalt(II) acetate (775 mg, 4.38 mmol) in MeOH (30 mL) under nitrogen at 20° C. The mixture was stirred at 20° C. for 30 min and at 0° C. for 1 h. The precipitated solid was filtered, washed with cold MeOH (2×30 mL), and dried in vacuo to give Co-S,S-cat (1.6 g, 73%) as a solid.

[0355] Step 2. To a solution of Co-S,S-cat (1.07 g, 1.78 mmol) in toluene (30 mL) was added AcOH (1.12 g, 18.7 mmol). The mixture was stirred at 20° C. for 30 minutes. The solution was concentrated in vacuo to give a solid. The resulting catalyst residue was dissolved in neat E-0 (100 g, 892 mmol) at 20° C., the reaction mixture was cooled to 0° C., and water (8.82 g, 490 mmol) was added dropwise. The mixture was warmed to 20° C. and stirred for 48 hours. E-1 (44 g) was isolated by distillation from the reaction mixture. 1 H NMR (400 MHz, DMSO-d6) δ 3.96 (s, 1H), 3.11-2.98 (m, 2H).

[0356] The ee of E-1 was determined by ring-opening the epoxide with benzylamine. E-1 (200 mg, 1.78 mmol) was added to dry benzylamine (190 mg, 1.78 mmol), and the mixture was stirred at 20 °C for 2 h. A solid precipitated, which was triturated from petroleum ether to give the product (260 mg, 67%) as a solid. The ee of this product was determined to be 100% by chiral HPLC (column: CD-PH 250*4.6 mm ID, 5 μm; mobile phase: 10% to 80% B in A (A: water with 0.069% TFA, B: acetonitrile); flow rate: 0.8 mL / min; column temperature: 30 °C). Example 9. Synthesis of Compound 5. [ka]

[0357] Step 1. To a solution of n-BuLi (0.704 mL, 2.5 M in hexanes, 1.76 mmol) in THF (0.5 mL) was added dropwise a suspension of B-7 (310 mg, 0.588 mmol) in THF (2.5 mL) at −65° C. under N, and the reaction was stirred at −65° C. for 30 min. A solution of E-1 (78.9 mg, 0.705 mmol) was added dropwise at −65° C. The mixture was stirred for an additional 30 min and then gradually warmed to 25° C. and stirred at 25° C. for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl (30 mL) and extracted with ethyl acetate (3×20 mL). The combined organic phase was washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to give E-2 (300 mg, crude) as a solid, which was used directly in the next step.

[0358] Step 2. To a solution of E-2 (300 mg, 0.469 mmol) and nickel(II) chloride (15.1 mg, 0.117 mmol) in dry methanol (20 mL) was added magnesium powder (454 mg, 18.7 mmol) with stirring under N at 50 °C to initiate continuous hydrogen evolution. The reaction mixture was stirred at 60 °C for 1 h. The reaction mixture was quenched dropwise with 2 M HCl (100 mL) at 10 °C until the solid dissolved. After extraction with EtOAc (2 × 150 mL), the combined organic layers were washed with saturated aqueous NaHCO (300 mL), brine (300 mL), dried over NaSO, filtered, and concentrated in vacuo to give a solid, which was purified by silica gel chromatography (PE:THF = 12:1) to give the product. The residue was recrystallized from MeCN (10 mL) to give compound 5 (41 mg, 18%) as a solid. 1H NMR (400 MHz, CDCl3) δ 3.75-3.65 (m, 1H), 2.10-1.95 (m, 3H), 1.90-1.75 (m, 2H), 1.73-1.66 (m, 5H), 1.56-1.30 (m, 14H), 1.29-1.01 (m, 5H), 1.00-0.85 (m, 3H), 0.84 (s, 3H), 0.67-0.60 (m, 4H). LCMS Rt=1.226 min (2.0 min chromatography), 30-90AB. Example 10. Synthesis of Compound 6. [ka]

[0359] Step 1. To a solution of n-BuLi (0.568 mL, 2.5 M in hexanes, 1.42 mmol) in THF (0.5 mL) was added dropwise a suspension of B-7 (250 mg, 0.474 mmol) in THF (2.5 mL) at −65° C. under N. After stirring at −65° C. for 30 min, a solution of (2S)-2-methyloxirane (32.9 mg, 0.568 mmol) was added dropwise at −65° C. The mixture was stirred for an additional 30 min and then gradually warmed to 25° C. and stirred at 25° C. for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl (30 mL) and extracted with ethyl acetate (3×20 mL). The combined organic phase was washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to give F-1 (250 mg, crude) as a solid, which was used directly in the next step.

[0360] Step 2. To a solution of F-1 (250 mg, 0.427 mmol) and nickel(II) chloride (13.7 mg, 0.106 mmol) in dry methanol (20 mL) was added magnesium powder (413 mg, 17.0 mmol) with stirring under N at 50 °C to initiate continuous hydrogen evolution. The reaction mixture was stirred at 60 °C for 1 h. The reaction mixture was quenched with 2 M HCl (100 mL), which was added dropwise at 10 °C until the solid dissolved. After extraction with EtOAc (2 × 150 mL), the combined organic layers were washed with saturated aqueous NaHCO (300 mL), brine (300 mL), dried over NaSO, filtered, and concentrated in vacuo to give a solid, which was purified by silica gel chromatography (PE / THF = 12 / 1) to give impure compound 6 (100 mg, containing 12% of the 22,23-olefin by NMR) as a solid. To a solution of impure compound 6 (100 mg, 0.224 mmol) in EtOAc (10 mL) was added Pd / C (26.5 mg, 0.224 mmol) under N to remove undesired olefin. The mixture was degassed under vacuum and purged with H several times. The mixture was stirred under H at 25 °C for 2 h. The mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by recrystallization from MeCN (10 mL) to give compound 6 (35 mg, 19%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 3.75-3.65 (m, 1H), 2.10-1.95 (m, 3H), 1.90-1.75 (m, 2H), 1.73-1.66 (m, 4H), 1.56-1.30 (m, 8H), 1.29-1.01 (m, 14H), 1.00-0.85 (m, 4H), 0.84 (s, 3H), 0.67-0.60 (m, 4H). LCMS Rt=1.222 min (2.0 min chromatography), 30-90AB, C 28 H 42 FO[M+H-HO] - MS ESI calculated value 427, observed value 427. Example 11. Synthesis of compounds 7, 7-A, and 7-B. [ka]

[0361] X-ray data for compound 7 confirmed the stereochemistry of compounds 7-A and 7-B.

[0362] Step 1: To a solution of compound G-1 (5.0 g, 12.8 mmol) in EtOAc (150 mL), Pd / C (1.0 g) was added, and the mixture was then stirred under hydrogen (50 psi) at 50 °C overnight. The mixture was filtered through a Celite pad, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 15:1) to give pure product G-2 (3.7 g, 74%).

[0363] 1 H NMR: (400 MHz, CDCl3) δ 3.66 (s, 3H), 3.53-3.62 (m, 1H), 2.40-2.30 (m, 1H), 2.26-2.18 (m, 1H), 1.97-1.62 (m, 6H), 1.60-1.20 (m, 13H), 1.18-0.93 (m, 6H), 0.92 (d, J=6.8Hz, 3H), 0.90-0.82 (m, 1H), 0.79 (s, 3H), 0.64-0.59 (m, 4H).

[0364] Step 2. To a solution of G-2 (10 g, 25.6 mmol) in DCM (200 mL) was added DMP (19.5 g, 46 mmol) at 25 °C. The mixture was stirred at 25 °C for 30 min. Water (80 mL) was added followed by NaHCO (20 g), and the mixture was filtered. The filtrate was extracted with DCM (100 mL), washed with NaSO (2 × 300 mL) and brine (2 × 300 mL), dried over NaSO, filtered, and concentrated in vacuo. Concentration gave the crude product G-3 (9 g) as a solid, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 3.66 (s, 3H), 2.41-2.29 (m, 1H), 2.27-2.16 (m, 1H), 2.10-1.91 (m, 3H), 1.88-1.62 (m, 6H), 1.52-0.98 (m, 16H), 0.97-0.87 (m, 4H), 0.84 (s, 3H), 0.73-0.63 (m, 4H).

[0365] Step 3. To a mixture of G-3 (7 g, 18.0 mmol) and CsF (5.46 g, 36.0 mmol) in THF (70 mL) was added TMSCF (5.11 g, 36.0 mmol) dropwise at 0 °C. The mixture was stirred and kept below 10 °C for 10 min. TBAF (45.0 mL, 1 M in THF, 45.0 mmol) was added at 10 °C, and the mixture was stirred and kept below 10 °C for 10 min. The mixture was then treated with water (200 mL) and extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (500 mL), dried over Na SO , filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EtOAc=5 / 1) to give G-4 (5.55 g, 67%), 4H), 0.84 (s, 3H), 0.73-0.63 (m, 4H).

[0366] Step 4. To a suspension of LiAlH (1.03 g, 27.4 mmol) in THF (80 mL) was added dropwise a solution of G-4 (6.3 g, 13.7 mmol) in THF (20 mL) at 0 °C under N. The reaction was stirred at 25 °C for 2 h. The reaction was quenched with water / THF (1 / 10, 40 mL), followed by the addition of 2 M HCl (100 mL) at 0 °C. The mixture was extracted with EtOAc (2 × 100 mL). The combined organic phase was washed with brine (300 mL), dried over NaSO, filtered, and concentrated to give G-5 (5 g, crude) as a solid. 1H NMR (400 MHz, CDCl3) δ 3.61 (s, 2H), 2.11-1.92 (m, 4H), 1.90-1.77 (m, 2H), 1.73-1.60 (m, 5H), 1.52-0.98 (m, 17H), 0.96-0.87 (m, 4H), 0.85 (s, 3H), 0.73-0.64 (m, 4H).

[0367] Step 5. To a solution of G-5 (3 g, 6.96 mmol) in DCM (30 mL) was added DMP (5.89 g, 13.9 mmol) at 20 °C. The reaction mixture was stirred at 20 °C for 20 min and quenched with saturated aqueous NaHCO (30 mL) at 20 °C. The mixture was filtered. The DCM layer was separated, and the aqueous phase was extracted with DCM (30 mL). The combined organic phase was washed with saturated aqueous NaSO (3 × 50 mL), brine (50 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was triturated from CHCN (5 mL) at 20 °C to give G-6 (1.3 g, 44%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 9.78-9.75 (t, J = 2.00 Hz, 1H), 2.51-2.20 (m, 2H), 2.11-1.74 (m, 6H), 1.74-0.97 (m, 19H), 0.96-0.87 (m, 4H), 0.85 (s, 3H), 0.73-0.67 (m, 1H), 0.65 (s, 3H).

[0368] Step 6. To a suspension of Mg (2 g, 82.2 mmol) and I2 (10 mg) in THF (2 mL) was added dropwise a solution of bromocyclobutane (5 g, 37.0 mmol) in THF (8 mL) at 60 °C. The mixture was stirred at 60 °C for 1 h. The mixture was diluted with THF (10 mL) and used directly. The Grignard reagent was added to a solution of G-6 (0.6 g, 1.40 mmol) in THF (5 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h and quenched with NH4Cl (10 mL, saturated aqueous solution). The mixture was extracted with EtOAc (3 × 20 mL). The organic layer was separated and concentrated in vacuo, and purified by silica gel (PE / EtOAc = 20 / 1 to 5 / 1) to give the crude product, which was recrystallized from MeCN / HO (5 / 2, 15 mL) to give compound 7 (250 mg, 37%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 3.49-3.38 (m, 1H), 2.40-2.25 (m, 1H), 2.1 0-1.90 (m, 5H), 1.90-1.60 (m, 9H), 1.57-1.18 (m, 14H), 1.17-0.96 (m, 6H), 0.96-0.86 (m, 4H), 0.84 (s, 3H), 0.73-0.62 (m, 4H). HPLC Rt = 6.10 min (8.0 min chromatography), 50-100 AB.C 29 H 46 FO[M+H-HO] + MS ESI calculated value 467, observed value 467.

[0369] Step 7. To a solution of compound 7 (200 mg, 0.412 mmol) in DCM (5 mL) was added pyridine (650 mg, 8.23 ​​mmol) and BzCl (347 mg, 2.47 mmol). The mixture was stirred at 25 °C for 1 h. The mixture was treated with HO (5 mL) and washed with HCl (10 mL, 1 M, aq.), NaHCO (10 mL, saturated aq.), dried over NaSO, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column (PE / EtOAc = 10 / 1) to give 300 mg of impure product. The impure product was separated by SFC (column: Chiralpak AD-3 50*4.6 mm ID, 3 μm); condition: Base-IPA; gradient: 5-40% B; flow rate: 4 mL / min) to give G-6-A (75 mg, 31%, t R = 5.282 min, 100% DE (Column: Chiralpak AD-3 150 × 4.6 mm ID, 3 μm, Mobile phase: A:CO₂B:iso-propanol (0.05% DEA), Gradient: 5% to 40% B for 5 min, hold at 40% for 2.5 min, then 5% B for 2.5 min, Flow rate: 2.5 mL / min, Column temperature: 35 °C)) and G-6-B (88 mg, 36%, t R = 4.827 min, 100% de (Column: Chiralpak AD-3 150 x 4.6 mm ID, 3 μm, Mobile phase: A:CO2, B:isopropanol (0.05% DEA), Gradient: 5% to 40% B in 5 min and hold at 40% for 2.5 min, then 5% B for 2.5 min, Flow rate: 2.5 mL / min, Column temperature: 35 °C).

[0370] Step 8a. To a solution of G-7-A (75 mg, 0.127 mmol) in THF (5 mL) and MeOH (1 mL) was added a suspension of LiOH.HO (399 mg, 9.52 mmol) in water (1 mL). The mixture was stirred at 60 °C for 24 h. After the organic solvent was removed in vacuo, the mixture was treated with HO (5 mL) and extracted with EtOAc (3 × 5 mL). The organic layer was washed with brine (2 × 15 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was triturated from CHCN (2 mL) at 25 °C to give compound 7-A (43 mg, 70%) as a solid.

[0371] 1 H NMR (400 MHz, CDCl3) δ 3.49-3.41 (m, 1H), 2.37-2.26 (m, 1H), 2.10-1.75 (m, 10H), 1.75-1.60 (m, 4H), 1.52-1.15 (m, 16H), 1.15-0.93 (m, 4H), 0.92-0.82 (m, 7H), 0.73-0.62 (m, 4H). HPLC Rt=6.78 min (8.0 min chromatography), 30-90AB. C 29 H 46 FO[M+H-HO] + MS ESI calculated value 467, observed value 467.

[0372] Step 8b. To a solution of G-7-B (88 mg, 0.149 mmol) in THF (5 mL) and MeOH (1 mL) was added a suspension of LiOH.HO (406 mg, 9.68 mmol) in water (1 mL). The mixture was stirred at 60 °C for 24 h. After removing the organic solvent in vacuo, the mixture was treated with HO (5 mL) and extracted with EtOAc (3 × 5 mL). The organic layer was washed with brine (2 × 15 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was triturated from CHCN (2 mL) at 25 °C to give compound 7-B (52 mg, 72%) as a solid. 1H NMR (400 MHz, CDCl3) δ 3.48-3.37 (m, 1H), 2.39-2.26 (m, 1H), 2.10-1.74 (m, 10H), 1.72-1.61 (m, 4H), 1.53-1.19 (m, 13H), 1.19-0.94 (m, 7H), 0.94-0.80 (m, 7H), 0.73-0.62 (m, 4H). HPLC Rt=6.78 min (8.0 min chromatography), 30-90AB C 29 H 46 FO[M+H-HO] + MS ESI calculated value 467.3495, measured Value 467.3. Example 12. Synthesis of Compound H-1 [ka]

[0373] To a suspension of Me3SI (3.93 g, 19.3 mmol) in THF (20 mL) was added a solution of t-BuOK (3.33 g, 29.8 mmol) in THF (10 mL) at 15 °C under N2. The suspension was stirred at 15 °C for 30 min. A solution of H-0 (2 g, 14.9 mmol) in THF (5 mL) was added dropwise at 15 °C. The mixture was stirred at 15 °C for 16 h. The mixture was quenched with saturated NH4Cl (50 mL) and extracted with EtOAc (3 × 20 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated to give H-1 (1.8 g, 82%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 2.72 (s, 2H), 2.20-1.85 (m, 8H). Example 13. Synthesis of Compound 8. [ka]

[0374] Step 1. To a solution of THF (5 mL) and BuLi (3.78 mL, 2.5 M in hexanes, 9.47 mmol) was added a solution of B-7 (2 g, 3.79 mmol) in THF (15 mL) at −70° C. After stirring at −70° C. for 1 h, a solution of H-1 (1.68 g, 5.68 mmol) in THF (5 mL) was added at −70° C. The mixture was stirred at −70° C. for an additional 1 h. The mixture was warmed to 25° C. and stirred for 16 h, and quenched by adding NH4Cl (50 mL, saturated aqueous solution). The mixture was extracted with EtOAc (2 × 30 mL). The organic layer was separated, dried over Na2SO4, filtered, concentrated, and purified by Combiflash (0–10% EtOAc in PE) to give H-2 (250 mg, 10%) as a solid, and 1.8 g of the starting material was recycled.

[0375] 1 H NMR (400 MHz, CDCl3) δ 8.00-7.92 (m, 2H), 7.73-7.65 (m, 1H), 7.63-7.52 (m, 2H), 3.62-3.55 (m, 1H), 2.37-2.28 (m, 1H), 2.15-1.94 (m, 4H), 1.94-1.85 (m, 6H), 1.85-1.55 (m, 5H), 1.55-1.43 (m, 6H), 1.43-1.10 (m, 10H), 1.10-0.90 (m, 3H), 0.90-0.70 (m, 6H), 0.70-0.57 (m, 1H), 0.55 (s, 3H).

[0376] Step 2. To a solution of H-2 (250 mg, 0.37 mmol) in MeOH (15 mL) was added Mg powder (355 mg, 14.8 mmol) at 55 °C. The mixture was stirred at 60 °C for 16 h. The mixture was quenched with HCl (50 mL, 1N) until the reaction became clear and extracted with DCM (2 × 30 mL). The combined organic phases were dried over NaSO, filtered, concentrated, and purified by flash column (0-10% EtOAc in PE) to give compound 8 (55 mg, 28%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 2.20-1.73 (m, 9H), 1.73-1.58 (m, 7H), 1.58-0.85 (m, 11H), 0.85-1.00 (m, 8H), 1.00-0.86 (m, 5H), 0.85 (s, 3H), 0.72-0.62 (m, 4H). LCMS Rt=1.286 min (2 min chromatography), 30-90AB, C 30 H 46 FO[M-HO+H] + MS ESI calculated value 517, measured value 517. Example 14. Synthesis of Compound 9. [ka]

[0377] To a suspension of Mg (1.37 g, 56.5 mmol) and I2 (10 mg) in THF (2 mL) was added dropwise a solution of 4-chlorotetrahydro-2H-pyran (2.72 g, 22.6 mmol) in THF (8 mL) at 60 °C. The mixture was stirred at 60 °C for 2 h. The mixture was diluted with THF (10 mL) and used directly. The Grignard reagent was added to a solution of G-6 (0.55 g, 1.28 mmol) in THF (5 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h and treated with NH4Cl (10 mL, saturated aqueous solution). The mixture was extracted with EtOAc (3 × 20 mL). The organic layer was separated, concentrated in vacuo, and purified by silica gel column (PE / EtOAc = 20 / 1 to 5 / 1) to give the crude product, which was recrystallized from CH3CN (10 mL) to give compound 9 (180 mg, 27%) as a solid. 1H NMR (400 MHz, CDCl3) δ 4.05-3.97 (m, 2H), 3.41-3.25 (m, 3H), 2.10-1.91 (m, 3H), 1.88-1.57 (m, 7H), 1.55-1.33 (m, 11H), 1.33-0.96 (m, 12H), 0.96-0.86 (m, 4H), 0.85 (s, 3H), 0.72-0.63 (m, 4H). HPLC Rt=4.73 min (8.0 min chromatography), 50-100AB.C 30 H 48 F3O2[M+H-H2O] + MS ESI calculated value 497, found value 497. Example 15. Synthesis of compound J-1. [ka]

[0378] To a mixture of trimethylsulfoxonium iodide (30.6 g, 150 mmol) in THF (100 mL) was added NaH (5.98 g, 60% in mineral oil). , 150 mmol) was added portionwise at 0 °C under N2. The mixture was stirred at 0 °C for 30 min. Dihydrofuran-3(2H)-one (10 g, 116 mmol) in DMSO (100 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The mixture was poured portionwise into ice water (500 mL) and extracted with DCM (2 × 500 mL). The combined organic phases were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated at 30 °C. The residue was purified by Combiflash (EtOAc in PE, 0% to 40%) to give J-1 (1.5 g, 13%) as an oil. 1H NMR (400 MHz, CDCl3) δ 4.11-3.90 (m, 3H), 3.66 (d, J = 10.0 Hz, 1H), 3.03 (d, J = 4.4 Hz, 1H), 2.94 (d, J = 4.0 Hz, 1H), 2.34-2.23 (m, 1H), 2.00-1.88 (m, 1H). Example 16. Synthesis of Compound 10. [ka]

[0379] Step 1. To a solution of n-BuLi (0.95 mL, 2.38 mmol, 2.5 M) in THF (2 mL) was added dropwise a suspension of A-7 (see Example 3) (500 mg, 0.95 mmol) in THF (5 mL) at −70° C. under N to give a suspension. After stirring at −70° C. for 30 min, a solution of J-1 (238 mg, 2.38 mmol) in THF (3 mL) was added. The reaction was then stirred at −70° C. for 10 min and at 20° C. for 16 h. The reaction was quenched with saturated NH4Cl (20 mL) and extracted with EtOAc (3×20 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product J-2 (500 mg) as a solid, which was used directly in the next step. LCMS Rt=0.925 min (1.5 min chromatography), 5-95AB, C 34 H 47 F3O5SNa[M+Na] + MS ESI calculated value 647, observed value 647.

[0380] Step 2. To a solution of J-2 (300 mg, 0.48 mmol) in 20 mL of dry methanol, magnesium turnings (466 mg, 19.2 mmol) (activated with 0.5% aqueous HCl, water, dry ethanol, and MTBE) and NiCl (12.4 mg, 0.96 mmol) were added with stirring under N at 55 °C to initiate continuous hydrogen evolution. After adding two more batches of 466 mg of magnesium turnings, most of the starting material was consumed. The reaction mixture was quenched with 2 M HCl (100 mL), which was added dropwise at 10 °C until the solid dissolved. After extraction with DCM (3 × 80 mL), the combined organic phase was washed with brine (100 mL), dried over Na SO , filtered, and concentrated. The residue was purified by Combiflash (0% to 50% EtOAc in PE) to give compound 10 (46 mg, 20%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 5.43-5.32 (m, 1H), 4.08-3.98 (m, 1H), 3.9 5-3.85 (m, 1H), 3.75-3.66 (m, 1H), 3.59-3.51 (m, 1H), 2.53-2.45 (m, 2H), 2.11-1.87 (m, 6H), 1.82-1.65 (m, 4H), 1.54-1.38 (m, 7H), 1.33-1.12 (m, 6H), 1.08-0.92 (m, 9H), 0.79-0.61 (m, 4H). LCMS Rt=1.121 min (2 min chromatography), 30-90AB, C 30 H 46 F3O3NNa[M+MeCN+Na] + MS ESI calculated value 548, observed value 548. Example 17. Synthesis of Compound 11. [ka]

[0381] Step 1. To a solution of n-BuLi (452 ​​μL, 2.5 M in hexanes, 1.13 mmol) in THF (0.5 mL) was added dropwise a suspension of B-7 (200 mg, 0.3797 mmol) in THF (2.5 mL) at −65° C. under N and stirred at −65° C. for 30 min. Then, diisopropylamine (114 mg, 1.13 mmol) was added at −65° C., followed by the dropwise addition of 1,6-dioxaspiro[2.5]octane (65.0 mg, 0.5695 mmol) at −65° C. The mixture was stirred for an additional 30 min and then gradually warmed to 25° C. and stirred at 25° C. for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl (30 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phase was washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to give K-1 (380 mg, crude) as a solid, which was used directly in the next step.

[0382] Step 2. To a solution of K-1 (0.348 g, 0.543 mmol) in MeOH (20 mL) was added Mg (0.520 g, 21.7 mmol) and NiCl (3.51 mg, 0.0271 mmol) at 60 °C. The mixture was stirred at 60 °C for 1 h. The reaction mixture was cooled to 25 °C. HCl (20 mL, 1 M in water) was added. The mixture was extracted with EtOAc (2 × 20 mL), washed with NaHCO (2 × 40 mL) and brine (2 × 40 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column (PE / EtOAc = 10 / 1 to 2 / 1) to give 66 mg of impure compound 11 as a solid, which was triturated from CHCN (5 mL) at 25 °C to give compound 11 (30 mg, 11%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 3.84-3.64 (m, 4H), 2.11-1.90 (m, 3H), 1.87-1.61 (m, 6H), 1.51-1.20 (m, 16H), 1.18-0.96 (m, 7H), 0.94-0.80 (m, 7H), 0.74-0.61 (m, 4H). LCMS Rt=1.170 min (2.0 min chromatography), 30-90AB, C 29 H 46 F3O2[M+H-H2O] + MS ESI calculated value 483, observed value 483. Example 18: Synthesis of Compound 1839 [ka]

[0383] Experiments with intermediate ST-200-INT_2 or A2 can be found in Example 3.

[0384] Synthesis of ST-200-CF3_1A [ka] A solution of ST-200-INT_2 (9.5 g, 30.4 mmol) and TMSCF3 (12.9 g, 91.2 mmol) in THF (50 mL) was added dropwise to a suspension of CsF (462 mg, 3.04 mmol) in THF (100 mL) at 0 °C within 30 min. The mixture was stirred at 10 °C for 16 h. TLC showed that starting material remained. The mixture was cooled to 0 °C. TBAF (3 mL, 1 M in THF, 3 mmol, Aldrich) was added to the mixture at 0 °C. The mixture was stirred at 10 °C for 1 h. TBAF (91.2 mL, 1 M in THF, 91.2 mmol) was added to the mixture. The mixture was stirred at 10 °C for another 1 h. The mixture was concentrated in vacuo. The residue was dissolved in EtOAc (100 mL), washed with water (3 × 100 mL), and concentrated in vacuo to give a crude product, which was combined with another batch of 9.5 g of ST-200-INT_2 and purified in four portions by silica gel column (PE: EtOAc = 30: 1 to 20: 1) to give ST-200-CF3_1B (2.3 g, 83% purity, 8% yield) and ST-200-CF3_1A (6.2 g, 32% purity, 8% yield). 3.0 g of impure ST-200-CF3_1A was used directly in the next step, and another 3.2 g was purified by silica gel column (PE: EtOAc = 30: 1 to 20: 1) and recrystallized from MeCN (10 mL) to give ST-200-CF3_1A (0.5 g, 94% purity). Note: 3 J H,CF3 ST-200-CF3_1A and ST-200-CF3_1B were identified from (FDCS).(J.Org.Chem.2015,80,1754). ST-200-CF3_1A: 1 H NMR (400 MHz, CDCl3) δ 5.43-5.33 (m, 1H), 4.85 (s, 1H); 4.71 (s, 1H); 2.49 (s, 2H); 2.11-1.97 (m, 4H), 1.95-1.32 (m, 14H), 1.30-0.98 (m, 7H), 0.59 (s, 3H). ST-200-CF3_1B: 1 H NMR (400 MHz, CDCl3) δ 5.54-5.41 (m, 1H), 4.86 (s, 1H); 4.72 (s, 1H); 2.78-2.65 (m, 1H); 2.18-1.97 (m, 3H), 1.95-1.35 (m, 16H), 1.32-0.98 (m, 7H), 0.59 (s, 3H).

[0385] Synthesis of ST-200-CF3_2A [ka] 9-BBN dimer (2.19 g, 9.01 mmol) was added to a solution of ST-200-CF3_1A (3 g, impure) in THF (35 mL). The mixture was stirred at 40 °C for 1 h. Next, EtOH (4.5 mL), NaOH (15.6 mL, 5 M, aq.), and HO (7.83 mL, 10 M, aq.) were added dropwise, and the mixture was cooled to 0 °C. The mixture was stirred at 50 °C for 1 h. After cooling, NaSO (100 mL, 10%, aq.) was added to the mixture. The mixture was extracted with EtOAc (100 mL). The organic layer was separated and purified using a silica gel column (PE: EtOAc = 10:1 to 7:1) to give ST-200-CF3_2A (1.2 g, 79% purity, 30% yield) as a solid. 1 H NMR (400 MHz, CDCl3) δ 5.42-5.32 (m, 1H), 3.64 (dd, J = 2.8, 10.4 Hz, 1H), 3.36 (dd, J = 6.8, 10.4 Hz, 1H), 2.50 (s, 2H), 2.32-1.92 (m, 4H), 1.92-1.70 (m, 4H), 1.70-1.29 (m, 8H), 1.29-0.91 (m, 11H), 0.71 (s, 3H).

[0386] Synthesis of ST-200-CF3_3A [ka] TsCl (1.14 g, 5.98 mmol) was added to a solution of ST-200-CF3_2A (1.2 g, 2.99 mmol) in DCM (5 mL) and py (3.5 mL). The mixture was stirred at 15 °C for 2 h. PE (10 mL) was added to the mixture. The mixture was washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, concentrated in vacuo, and purified by silica gel column (PE:DCM:EtOAc = 5:1:0.3 to 5:1:0.4) to give ST-200-CF3_3A (1.05 g, 64%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 5.40-5.33 (m, 1H), 3.97 (dd, J = 2.8, 9.2 Hz, 1H), 3.77 (dd, J = 6.4, 9.2 Hz, 1H), 2.48 (s, 2H), 2.45 (s, 3H), 2.10-1.88 (m, 5H), 1.82-1.35 (m, 9H), 1.30-0.82 (m, 12H), 0.64 (s, 3H).

[0387] Synthesis of ST-200-CF3_4A [ka] KI (1.25 g, 7.56 mmol) was added to a solution of ST-200-CF3_3A (1.05 g, 1.89 mmol) in DMF (5 mL). The mixture was stirred at 50 °C for 1 h. PhSO2Na (0.93 g, 5.67 mmol) was added to the mixture. The mixture was stirred at 50 °C for 2 h. Water (10 mL) and DCM (30 mL) were added to the mixture. The organic layer was separated, dried over Na2SO4, filtered, concentrated in vacuo, and triturated from PE / DCM (10 mL, 5:1) to give ST-200-CF3_4A (600 mg, 61%) as a solid. 1H NMR (400 MHz, CDCl3) δ 7.98-7.87 (m, 2H), 7.70-7.52 (m, 3H), 5.39-5.31 (m, 1H), 3.14 (d, J = 14.4 Hz, 1H), 2.85 (dd, J = 9.6, 14.0 Hz, 1H), 2.48 (s, 2H), 2.20-1.88 (m, 5H), 1.88-1.68 (m, 4H), 1.60-1.33 (m, 5H), 1.30-0.82 (m, 12H), 0.64 (s, 3H).

[0388] Synthesis of E-322_6_1 [ka] Diisopropylamine (3.76 mmol, 380 mg) was added to THF (2 mL) at −70° C. under N2, followed by n-BuLi (3.42 mmol, 1.36 mL, 2.5 M in hexanes, 3.0 equiv.). The reaction was warmed to 15° C. and then recooled to −70° C. A suspension of ST-200-CF3_4A (1.14 mmol, 600 mg) in THF (5 mL) was added dropwise to give a suspension. After stirring at −70° C. for 30 min, a solution of 2,2-dimethyloxirane (2.28 mmol, 218 mg, 2.0 equiv.) in THF (1 mL) was added over 5 min (slightly exothermic, keeping the internal T<−70° C.). The reaction was then stirred at 15° C. for 12 h. The reaction was quenched with saturated NH4Cl (30 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give ST-200-CF3-5A (600 mg, crude) as a foam.

[0389] Synthesis of 1839 [ka] Mg powder (960 mg, 40 mmol) was added to a solution of E-322_6_1 (600 mg, 1 mmol) in MeOH (10 mL) at 55 °C. The reaction mixture was stirred at 60 °C for 2 h under N. The mixture was quenched with HCl (100 mL, 2 M) until the reaction became clear and extracted with DCM (3 × 20 mL). The combined organic phase was washed with saturated NaHCO3 (50 mL), dried over Na2SO4, filtered, concentrated and purified by Combiflash (0-10% EtOAc in PE) to give 170 mg of impure product, which was purified again by preparative HPLC (column: DuraShell 150*25 mm*5 um), gradient: 75-100% B (A=0.05% HCl / HO, B=MeCN), flow rate: 30 mL / min) to give 1839 (66 mg, 14%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 5.37-5.36 (m, 1H), 2.48 (s, 2H), 2.10-1.92 (m, 4H), 1.90-1.70 (m, 3H), 1.62-1.58 (m, 2H), 1.56-1.35 (m, 7H), 1.34-1.22 (m, 3H), 1.21-1.07 (m, 10H), 1.06 (s, 3H), 1.05-0.98 (m, 2H), 0.93 (d, J = 6.8 Hz, 3H), 0.68 (s, 3H). LCMS Rt=1.277 min (2.0 min chromatography), 30-90AB, 100% purity, C 27 H 42 FO[M+H-HO] + MS ESI calculated value 439, measured value 439. Example 19: Synthesis of 1967 [ka]

[0390] The synthesis of ST-200-CF3_6C or B7 can be found in Example 5.

[0391] Synthesis of 200-DA-C24_8_2 [ka] Sodium hydride (18.0 g, 60% in mineral oil, 452 mmol) was added portionwise to a mixture of trimethylsulfoxonium iodide (92.2 g, 452 mmol) in THF (300 mL) under N at 0 °C. The mixture was stirred at 0 °C for 30 min. Dihydrofuran-3(2H)-one (30 g, 348 mmol) in DMSO (300 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. The mixture was poured portionwise into ice-water (500 mL) and extracted with DCM (2 × 500 mL). The combined organic phase was washed with brine (500 mL), dried over Na SO , filtered, and concentrated at 30 °C to give 200-DA-C24_8_2 (32 g, crude) as an oil. From the residue, 3 g was purified by column (Al2O3, PE) to give 200-DA-C24_8_2 (0.6 g) as an oil. 1 H NMR (400 MHz, CDCl3) δ 4.09-3.90 (m, 4H), 3.03 (d, J = 4.4 Hz, 1H), 2.93 (d, J = 4.4 Hz, 1H), 2.28 (td, J = 8.0, 13.6 Hz, 1H), 1.93 (m, 1H).

[0392] Synthesis of ST-200-35-7_1 [ka] A suspension of ST-200-CF3_6C (500 mg, 0.9493 mmol) in THF (2.5 mL) was added dropwise to a solution of n-BuLi (1.13 mL, 2.5 M in hexane, 2.84 mmol) in THF (0.5 mL) under N2 at −65 °C. The mixture was stirred at −65 °C for 30 min. Diisopropylamine (286 mg, 2.84 mmol) was added at −65 °C. Next, 200-DA-C24_8_2 (95.0 mg, 0.9493 mmol) was added dropwise at −65 °C. The mixture was stirred for an additional 30 min and then gradually warmed to 25 °C. The reaction mixture was stirred at 25 °C for 16 h, quenched with saturated aqueous NH4Cl (30 mL), and extracted with ethyl acetate (3 × 20 mL). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo to give ST-200-35-7_1 (900 mg, crude) as a solid, which was used directly in the next step.

[0393] 1967 Synthesis [ka] Mg (686 mg, 28.6 mmol) was added to a solution of crude ST-200-35-7_1 (900 mg) in MeOH (10 mL). The reaction mixture was then stirred at 60 °C under N for 2 h. Aqueous HCl (10 mL, 4 M) was added to the reaction mixture, which was then extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel chromatography (PE / EtOAc = 30 / 1 to 10 / 1) to give impure 1967 (460 mg) as a solid. Impure 1967 (460 mg) was purified by recrystallization from MeCN (2 mL) to give 1967 (175 mg) as a solid. The mother liquor was concentrated in vacuo to give impure ST-200-35-7 (220 mg) as a solid. 1H NMR (400 MHz, CDCl3) δ 4.10-4.00 (m, 1H), 3.95-3.85 (m, 1H), 3.75-3.65 (m, 1H), 3.55-3.50 (m, 1H), 2.10-2.00 (m, 2H), 2.00-1.85 (m, 3H), 1.85-1.75 (m, 2H), 1.75-1.56 (m, 5H), 1.55-1.40 (m, 6H), 1.40-1.20 (m, 7H), 1.20-1.00 (m, 5H), 1.00-0.88 (m, 4H), 0.85 (s, 3H), 0.75-0.68 (m, 1H), 0.66 (s, 3H). LCMS Rt=1.148 min (2.0 min chromatography), 30-90AB, 100% purity, C 30 H 48 F3NO3Na[M+MeCN+Na] + MS ESI calculated value 550, measured value 550. Example 20: Synthesis of 2080 and 2081 [ka]

[0394] X-ray data confirmed the stereochemistry.

[0395] Experimental work on intermediate DA-35-6 can be found in Example 14.

[0396] Synthesis of DA-35-4_1A and DA-35-4_1B [ka] Py (498 mg, 6.30 mmol) and BzCl (531 mg, 3.78 mmol) were added to a solution of DA-35-6 (130 mg, 0.252 mmol) in DCM (5 mL). The mixture was stirred at 25 °C for 6 h and quenched by adding HO (5 mL). The mixture was washed with HCl (10 mL, 1 M, aq.), NaHCO (10 mL, saturated aq.), dried over NaSO, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column (PE: EtOAc = 20:1 to 10:1) to give DA-35-4_1 (170 mg, impure). Impure DA-35-4_1 (170 mg) was separated by SFC (column: Chiralpak AD-3 50*4.6 mm ID, 3 μm); conditions: Base-IPA; gradient: 5-40% B; flow rate: 4 mL / min) to give DA-35-4_1A (56 mg, 36%, Rt = 4.889 min, 100% de) and DA-35-4_1B (80 mg, 51%, Rt = 5.283 min, 100% de). DA-35-4_1A: 1 H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.0 Hz, 2H), 7.56 (t, J = 8.0 Hz, 1H), 7.45 (t, J = 8.0 Hz, 2H), 5.04-4.94 (m, 1H), 4.06-3.94 (m, 2H), 3.44-3.32 (m, 2H), 2.10-1.84 (m, 4H), 1.84-1.58 (m, 8H), 1.53-1.23 (m, 12H), 1.22-0.94 (m, 8H), 0.94-0.80 (m, 7H), 0.72-0.57 (m, 4H). DA-35-4_1B: 1 H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.0 Hz, 2H), 7.56 (t, J = 8.0 Hz, 1H), 7.45 (t, J = 8.0 Hz, 2H), 5.05-4.96 (m, 1H), 4.03-3 .93 (m, 2H), 3.44-3.30 (m, 2H), 2.10-1.59 (m, 12H), 1.53-1.23 (m, 12H), 1.22-0.94 (m, 8H), 0.93-0.81 (m, 7H), 0.72-0.60 (m, 4H).

[0397] 2080 synthesis [ka] A solution of LiOH.HO (284 mg, 6.78 mmol) in water (1 mL) was added to a solution of DA-35-4_1A (56 mg, 0.090 mmol) in THF (5 mL) and MeOH (1 mL). The mixture was stirred at 50 °C for 20 h. The mixture was concentrated in vacuo and treated with HO (5 mL). The mixture was extracted with EtOAc (3 × 5 mL). The organic layer was washed with brine (2 × 15 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was triturated with MeCN (2 mL) at 25 °C to afford 2080 (12 mg, 26%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 4.05-3.95 (m, 2H), 3.40-3.25 (m, 3H), 2.05-1.95 (m, 2H), 1.85-1.80 (m, 2H), 1.75-1.25 (m, 17H), 1.24-0.90 (m, 16H), 0.89-0.75 (m, 3H), 0.65-0.60 (m, 4H). LCMS Rt=1.205 min (2.0 min chromatography), 30-90AB, 100% purity, C 30 H 48 F3O2[M+H-H2O] - MS ESI calculated value 497, found value 497.

[0398] Synthesis of 2081 [ka] A suspension of LiOH.HO (405 mg, 9.67 mmol) in water (1 mL) was added to a solution of DA-35-4_1B (80 mg, 0.129 mmol) in THF (5 mL) and MeOH (1 mL). The mixture was stirred at 50 °C for 20 h. The mixture was concentrated in vacuo and treated with HO (5 mL). The mixture was extracted with EtOAc (3 × 5 mL). The organic layer was washed with brine (2 × 15 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was triturated with MeCN (2 mL) at 25 °C to afford 2081 (32 mg, 48%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 4.05-3.95 (m, 2H), 3.40-3.25 (m, 3H), 2.05-1.90 (m, 4H), 1.89-1.60 (m, 8H), 1.59-1.35 (m, 10H), 1.34-0.95 (m, 11H), 0.94-0.75 (m, 7H), 0.65-0.60 (m, 4H). LCMS Rt=1.205 min (2.0 min chromatography), 30-90AB, 100% purity, C 30 H 48 F3O2[M+H-H2O] - MS ESI calculated value 497, found value 497. Example 21: Synthesis of 2184 [ka]

[0399] The synthesis of ST-200-CF3_6C or B7 can be found in Example 5.

[0400] Synthesis of 200-TBU-E_2 [ka] 200-TBU-E_1 (131 g, 998 mmol) was dissolved in 1690 mL of 5 N hydrochloric acid. The mixture was cooled to 0 °C, and a pre-cooled solution of sodium nitrite (109 g, 1.59 mol) in 400 mL of water was added dropwise, and the reaction mixture was then maintained below 5 °C. After 5 h, the mixture was stirred at 25 °C for 12 h. Solid sodium carbonate (100 g) was carefully added in small portions. The reaction mixture was extracted with isopropyl ether (500 mL × 2). The combined organic phases were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was isolated by distillation to give 200-TBU-E_2 (48 g, 32%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 4.12 (s, 1H), 1.13 (s, 9H).

[0401] Synthesis of 200-TBU-E_2 [ka] LiAlH4 (14.4 g, 381 mmol) was added to a solution of 200-TBU-E_2 (48 g, 318 mmol) in THF (500 mL) at 0 °C. The mixture was warmed to 25 °C and stirred at 25 °C for 30 min. Water / THF (100 mL, 1 / 1) was added, and the pH was adjusted to 2–3 with HCl (1 mol / L). The mixture was extracted with EA (2 × 500 mL), washed with brine (2 × 200 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give 200-TBU-E_3 (36 g, crude) as a solid. This product was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ 3.92-3.86 (m, 2H), 3.68-3.63 (m, 1H), 1.04 (s, 9H).

[0402] Synthesis of 200-TBU-E_4 [ka] 200-TBU-E_3 (16 g, 117 mmol) was added to a solution of potassium hydroxide (13.1 g, 234 mmol) in water (13 ml) at 0 °C. The ice bath was replaced with a water bath at 20 °C. As the cyclization reaction proceeded, a precipitate of potassium chloride formed. After 10 min, the bath temperature was slowly increased to 50 °C. The product was isolated by distillation to give 200-TBU-E_4 (6 g, 51.2%) as an oil. After UV protection, 100% ee was obtained. 1 H NMR (400 MHz, CDCl3) δ 2.73-2.71 (m, 1H), 2.64-2.63 (m, 1H), 2.62-2.59 (m, 1H), 0.91 (s, 9H).

[0403] A method for checking the ee of chiral epoxides [ka] n-BuLi (2.5 M, 1.99 mmol, 0.8 mL) was added dropwise to a solution of (methylsulfonyl)benzene (342 mg, 2.19 mmol) in THF (5 mL) at −70° C. under N. After stirring at −70° C. for 30 min, a solution of 200-TBU-E_4 (100 mg, 0.998 mmol) was added. The reaction was then stirred at 25° C. for 12 h. The mixture was poured into ice water (100 mL) and extracted with EA (2×50 mL). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EA=5 / 1) to give 200-TBU-E_4A (80 mg, 31.3%) as an oil. The ee% of the product was determined to be 100% by chiral HPLC.

[0404] Synthesis of DA-31-2_1 [ka] n-BuLi (0.416 mL, 2.5 M, 1.03 mmol) was added to a solution of diisopropylamine (110 mg, 1.09 mmol) in THF (1 mL) at −70° C. under N. The resulting mixture was stirred at 0° C. for 30 min. The mixture was recooled to −70° C. To this mixture was added ST-200-CF3_6C (250 mg, 0.474 mmol) in THF (2 mL) at −70° C. The reaction mixture was stirred at −70° C. for 1 h. (R)-2-(tert-butyl)oxirane (56.8 mg, 0.568 mmol) in THF (1 mL) was added at −70° C. The reaction mixture was slowly warmed to 15° C. and stirred at 15° C. for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl (20 mL) at 0° C. The mixture was extracted with EtOAc (2 × 20 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give crude DA-31-2_1 (300 mg) as a solid. 1 H NMR (400 MHz, CDCl3) δ 7.95-7.85 (m, 2H), 7.68-7.63 (m, 1H), 7.60-7.50 (m, 2H), 3.45-3.35 (m, 2H), 3.25-3.15 (m, 1H), 2.60-2.55 (m, 1H), 2.10-1.60 (m, 6H), 1.55-1.20 (m, 11H), 1.20-1.00 (m, 7H), 0.93 (s, 9H), 0.90-0.80 (m, 5H), 0.70-0.50 (m, 3H), 0.45 (s, 3H).

[0405] Synthesis of DA-31-2 [ka] Mg (229 mg, 9.55 mmol) was added to a solution of DA-31-2_1 (300 mg, 0.478 mmol) in MeOH (5 mL). The reaction was then stirred at 60 °C under N for 2 h. Aqueous HCl (10 mL, 4 M) was added to the reaction mixture, which was then extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel chromatography (PE / EtOAc = 30 / 1 to 10 / 1) to give impure DA-31-2 (100 mg, impure) as a solid. Dry Pd(OH) / C (50 mg) was added to a solution of DA-31-2 (100 mg, impure, 0.205 mol) in MeOH / THF = 1 / 1 (4 mL). The reaction mixture was then stirred at 50° C. under H and 50 psi for 16 h. The reaction mixture was filtered through a pad of Celite and washed with THF (3×5 mL). The combined organic layers were concentrated in vacuo to give crude DA-31-2 (85 mg) as a solid, which was purified by recrystallization from MeCN (2 mL) to give DA-31-2 (60 mg, 71%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 3.20-3.05 (m, 1H), 2.10-1.90 (m, 3H), 1.90-1.60 (m, 7H), 1.55-1.40 (m, 5H), 1.40-1.10 (m, 14H), 1.10-1.00 (m, 3H), 0.93 (s, 9H), 0.89 (s, 3H), 0.75-0.66 (m, 1H), 0.65 (s, 3H). LCMS Rt=1.356 min (2.0 min chromatography), 30-90AB, purity 99%, C 29 H 48 FO[M-HO+H] + MS ESI calculated value 469, observed value 469. Example 22: Synthesis of 2285 [ka]

[0406] The synthesis of ST-200-CF3_6C or B7 can be found in Example 5.

[0407] Synthesis of ST-200-3CF3-A7R_1 [ka] A suspension of ST-200-CF3_6C (250 mg, 0.475 mmol) in THF (2.5 mL) was added dropwise to a solution of n-BuLi (568 μL, 2.5 M in hexane, 1.42 mmol) in THF (0.5 mL) under N2 at −78 °C. The mixture was stirred at −78 °C for 30 min. A solution of 2-(methyl)oxirane (41.3 mg, 0.712 mmol) was added dropwise at −78 °C. The mixture was stirred for an additional 30 min and then gradually warmed to 25 °C. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl (30 mL) and extracted with EtOAc (3 × 20 mL). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give ST-200-3CF3-A7R_1 (340 mg, crude) as a solid, which was used directly in the next step.

[0408] Synthesis of 2285 [ka] Mg powder (556 mg, 23.2 mmol) was added to a solution of ST-200-3CF3-A7R_1 (340 mg, 0.581 mmol) in dry methanol (30 mL) under N2 at 60 °C. The reaction mixture was quenched by dropwise addition of 2 M HCl (50 mL) at 10 °C until the solid dissolved. After extraction with EtOAc (2 × 50 mL), the organic layer was washed with saturated NaHCO3 (50 mL), brine (50 mL), and After drying over NaSO, filtration, and concentration, the residue was purified by flash column chromatography eluting with PE / EtOAc = 20 / 1 to 5 / 1 to give 2285 (80 mg, impure, containing some 22-23 olefin) as a solid, which was used in the next step without further purification.

[0409] Synthesis of ST-200-3CF3-A7R [ka] Pd(OH) (20%, 126 mg, 0.180 mmol) was added to a solution of 2285 (80 mg, 0.180 mmol) in MeOH / THF (10 mL / 10 mL) under Ar. After degassing three times with N and H, the reaction mixture was stirred under an H atmosphere (50 psi) at 50 °C for 16 h. The desired product was formed, the catalyst was removed by vacuum, and the filtrate was concentrated to give 2285 (50 mg, impure) as a solid, which was triturated with MeCN (3 mL) at 25 °C to give 2285 (36 mg, 45%) as a solid. 2285 1 H NMR (400MHz ,CDCl3) δ 3.74-3.72 (m, 1H), 2.08-2.06 (m, 1H), 2.00-1.91 (m, 2H), 1.88-1.75 (m, 2H), 1.74-1.59 (m, 3H), 1.52-1.22 (m, 13H), 1.21-0.96 (m, 10H), 0.95-0.86 (m, 4H), 0.85 (s, 3H), 0.73-0.62 (m, 4H) LCMS Rt=1.199 min (2 min chromatography), 30-90AB, 100% purity, C 26 H 42 MS ESI calculated value of FO[M+H-H2O]+: 427, found value: 427. Example 23: Synthesis of 2392 [ka]

[0410] Experiments with intermediate ST-200-CF3_4A or A7 can be found in Example 3.

[0411] Synthesis of ST-200-3CF3-C14_1 [ka] BuLi (0.476 mL, 2.5 M in hexane, 1.19 mmol) was added to THF (0.5 mL). A solution of ST-200-CF3_4A (250 mg, 0.476 mmol) in THF (3 mL) was added at −70° C. The mixture was stirred at −70° C. for 1 h. 6,6-Difluoro-1-oxaspiro[2.5]octane (210 mg, 1.42 mmol) was added at −70° C. The mixture was stirred at −70° C. for an additional 1 h. The mixture was warmed to 25° C. and stirred for 16 h. NH4Cl (50 mL, saturated aqueous solution) was added to the mixture, and then the mixture was extracted with EtOAc (2 × 30 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated to give ST-200-3CF3-C14_1 (300 mg, crude) as a solid, which was used directly in the next step.

[0412] Synthesis of 2392 [ka] A solution of ST-200-31-15_1 (300 mg, 0.445 mmol) in MeOH (20 mL) was heated at 55 °C. Mg powder (427 mg, 17.8 mmol) was added in one portion at 55 °C. The mixture was refluxed at 65 °C for 1 h. The mixture was quenched with HCl (50 mL, 1N) until the reaction became clear, and then extracted with DCM (2 × 30 mL). The combined organic phase was dried over Na2SO4, filtered, concentrated, and purified by flash column (0-10% EtOAc in PE) to give impure product (110 mg), which was purified again by SFC (Column: AD (250 mm * 30 mm, 5 μm), Gradient: 35-35% B (A = 0.1% NH3 / HO, B = MeOH), Flow rate: 60 mL / min) to give 2392 (72 mg, 30%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 5.38-5.35 (m, 1H), 2.49 (s, 2H), 2.20-1.81 (m, 9H), 1.80-1.71 (m, 3H), 1.70-1.58 (m, 5H), 1.56-1.36 (m, 7H), 1.35-1.22 (m, 2H), 1.20-1.08 (m, 4H), 1.06 (s, 3H), 1.04-0.92 (m, 6H), 0.68 (s, 3H). LCMS Rt=1.248 min (2.0 min chromatography), 30-90AB, 100% purity, C 30 H 44 FO[M+H-HO] + MS ESI calculated value 515, measured value 515. Example 24: Synthesis of 2499 [ka]

[0413] The synthesis of DA-31-10_2 can be found in Example 11.

[0414] Synthesis of 2499 [ka] To a suspension of LiAlH (1.03 g, 27.4 mmol) in THF (80 mL) was added dropwise a solution of DA-31-10_2 (6.3 g, 13.7 mmol) in THF (20 mL) at 0 °C under N. The reaction was stirred at 25 °C for 2 h. The reaction was quenched with water / THF (1 / 10, 40 mL). To the mixture was added 2 M HCl (100 mL) at 0 °C and extracted with EtOAc (2 × 100 mL). The combined organic phase was washed with brine (300 mL), dried over NaSO, filtered, and concentrated to give 2499 (5 g, crude) as a solid. 100 mg of impure DA-31-10_3 was triturated with CHCN (5 mL) at 25 °C for 3 h to give 2499 (52 mg, 52%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 3.70-3.50 (m, 2H), 2.10-1.90 (m, 3H), 1.85-1.75 (m, 2H), 1.70-1.60 (m, 4H), 1.50-1.20 (m, 14H), 1.15-0.80 (m, 12H), 0.70-0.60 (m, 4H). LCMS Rt=1.179 min (2 min chromatography), 30-90AB_E, purity 100%, C 25 H 40 MS ESI calculated value of FO[M+H-H2O]+: 413, observed value: 413. Example 25: Synthesis of 2500 [ka]

[0415] Experimental work on intermediate ST-200-CF3_4A can be found in Example 3.

[0416] Synthesis of ST-200-31-6_1 [ka] n-BuLi (568 μL, 2.5 M in hexane, 1.42 mmol) was added to a solution of diisopropylamine (143 mg, 1.42 mmol) in THF (0.5 mL) under N at −78 °C. A suspension of ST-200-CF3-4A (250 mg, 0.476 mmol) in THF (2.5 mL) was added dropwise. The mixture was stirred at −78 °C for 30 min. A solution of 2-(tert-butyl)oxirane (71.5 mg, 0.715 mmol) was added dropwise at −78 °C. The mixture was stirred for an additional 30 min and then gradually warmed to 25 °C. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl (30 mL) and extracted with EtOAc (3 × 20 mL). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give ST-200-31-6_1 (350 mg, crude) as a solid, which was used directly in the next step.

[0417] 2500 Synthesis [ka]

[0418] A solution of ST-200-31-6_1 (350 mg, 0.6081 mmol) in MeOH (25 mL) was heated at 60 °C. Mg powder (584 mg, 24.3 mmol) was added in four portions at 60 °C. The mixture was stirred at 60 °C for 1 h. The mixture was quenched with HCl (50 mL, 2 M) until the reaction became clear and extracted with DCM (2 × 50 mL). The combined organic phases were dried over Na2SO4, filtered, concentrated, and purified by flash column (0–10% EtOAc in PE) to give 112 mg of impure product as a solid, which was triturated with MeCN (3 mL) at 25 °C to give 70 mg as a solid. The 70 mg of product was dissolved in THF (8 mL) and treated with Lindlar (100 mg) under N2. The mixture was degassed under vacuum and purged with H (15 psi) several times. The mixture was stirred under H (15 psi) at 25 °C for 2 h. The mixture was filtered, and the filter was concentrated in vacuo. The residue was purified by flash column (0-20% EtOAc in PE) to give pure 2500 (20 mg) as a solid. 1 H NMR (CDCl3,400MHz) δ 5.40-5.30 (m, 1H), 3.20-3.00 (m, 1H), 2.50-2.45 (s, 2H), 2.05-2.00 (m, 4H), 1.96-1.33 (m, 13H), 1.33-1.20 (m, 7H), 1.20-0.80 (m, 16H), 0.68 (s, 3H). LCMS Rt=1.404 min (2 min chromatography), 30-90AB, 100% purity, C 28 H 46 FO[M-HO+H] + MS ESI calculated value 467, observed value 467. Example 26: Synthesis of 2602 [ka]

[0419] Experiments with intermediate ST-200-CF3_4A or A7 can be found in Example 3.

[0420] Synthesis of ST-200-3CF3_C7S_1 [ka] A suspension of ST-200-CF3_4A (250 mg, 0.476 mmol) in THF (2.5 mL) was added dropwise to a solution of n-BuLi (0.568 mL, 2.5 M in hexane, 1.42 mmol) in THF (0.5 mL) under N2 at −65 °C. This mixture was added diisopropylamine (143 mg, 1.42 mmol) and stirred at −65 °C for 30 min. A solution of (S)-2-methyloxirane (33.1 mg, 0.571 mmol) was added dropwise at −65 °C. The mixture was stirred for an additional 30 min and then gradually warmed to 25 °C. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl (30 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give ST-200-3CF3-C7S_1 (250 mg, crude) as a solid, which was used directly in the next step.

[0421] Synthesis of 2602 [ka] Mg powder (415 mg, 17.1 mmol) was added to a solution of ST-200-3CF3-C7S_1 (250 mg, 0.428 mmol) and nickel(II) chloride (13.8 mg, 0.107 mmol) in dry methanol (20 mL) under N2, and the mixture was stirred at 50 °C to initiate continuous hydrogen evolution. The reaction mixture was stirred at 60 °C for 1 h. Then, the reaction mixture was quenched with 2 M HCl (100 mL), which was added dropwise at 10 °C until the solid dissolved. After extraction with EtOAc (2 × 150 mL), the combined organic layers were washed with saturated aqueous NaHCO3 (300 mL), brine (300 mL), dried over Na2SO4, filtered, and concentrated in vacuo to remove the solid. The resulting 2602 was purified by silica gel chromatography (PE: EtOAc = 4:1) to give 100 mg of a solid (the residue contained 13% of the 22,23 alkene). The impure residue was dissolved in THF (20 mL), and Lindlar (15.9 mg, 0.225 mmol) was added under N2. The mixture was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 at 25 °C for 2 h. The mixture was filtered, and the filter was concentrated in vacuo. The residue was purified by SFC (column: C2 250 mm * 30 mm, 10 μm), gradient: 35-35% B (A = 0.1% NH3 / H2O, B = EtOH), flow rate: 50 mL / min) to give 2602 (16 mg, 54%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 5.40-35 (m, 1H), 3.75-3.65 (m, 1H), 2.50-2.45 (m, 2H), 2.10-1.70 (m, 7H), 1.69-1.50 (m, 6H), 1.49-1.20 (m, 10H), 1.19-0.90 (m, 11H), 0.68 (s, 3H). LCMS Rt=1.202 min (2.0 min chromatography), 30-90AB, 100% purity, C 26 H 40 FO[M+H-HO] - MS ESI calculated value 425, measured value 425. Example 27: Synthesis of 2706 and 2707 [ka]

[0422] Experimental study of intermediate ST-200-CF3_4A can be found in Example 3. ST-200-35-7 can be found in Example 19. X-ray confirmed the stereochemistry of 2707.

[0423] Synthesis of ST-200-35-8A / 8B [ka] BzCl (258 mg, 1.84 mmol) was added to a solution of ST-200-35-7 (300 mg, 0.616 mmol) in pyridine (5 mL) at 0 °C. The mixture was stirred at 0 °C for 1 hour. Water (10 mL) was added to the mixture at 0 °C and extracted with DCM (3 × 10 mL). The organic layer was washed with 1 M HCl (10 mL), saturated Na2CO3 (10 mL), and brine. The mixture was dried over anhydrous Na2SO4 and concentrated in vacuo to give a residue. The residue was purified by preparative TLC (PE / EA = 5 / 1) to give a mixture. This mixture was separated twice by SFC (instrument: MG-II; method: column: AD (250 mm * 30 mm, 5 μm); conditions: 0.1% NH3H2O ​​ETOH; start B: 40%; end B: 40%; flow rate (ml / min): 60; injection: 90) to give peak 1 (Rt = 5.134 min) ST-200-35-8B (44 mg, 12%) and peak 2 (Rt = 5.766 min) ST-200-35-8A (38 mg, 10%) as solids. ST-200-35-8B: SFC Rt=5.134 min (10.0 min chromatography), AD_3_EtOH_DEA_5_40_25ML, 100% de. ST-200-35-8A:

[0424] Synthesis of 2706 [ka] MeOH (0.2 mL), water (0.2 mL), and LiOH.HO (31.2 mg, 0.744 mmol) were added to a solution of ST-200-35-8B (44 mg, 0.0744 mmol) in THF (0.4 mL). The mixture was stirred at 50 °C for 16 h. EtOAc (5 mL) and water (2 mL) were added to the mixture. The organic layer was separated, dried over NaSO, filtered, concentrated in vacuo, and triturated from MeCN (1 mL) to give 2706 (24 mg, 66%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 4.02 (q, J = 8.0 Hz, 1H), 3.93-3.83 (m, 1H), 3.69 (d, J = 9.2 Hz, 1H), 3.55 (d, J = 9.2 Hz, 1H), 2.10-1.79 (m, 7H), 1.75-1.59 (m, 5H), 1.55-0.99 (m, 18H), 0.98-0.88 (m, 4H), 0.85 (s, 3H), 0.75-0.60 (m, 4H). HPLC Rt=3.97 min (8.0 min chromatography), 50-100_AB_E, 100% purity. MS C 28 H 44 F3O2[M+H-H2O] + MS ESI calculated value 469.3288, found value 469.3244.

[0425] Synthesis of 2707 [ka] MeOH (0.2 mL), water (0.2 mL), and LiOH.HO (26.9 mg, 0.642 mmol) were added to a solution of ST-200-35-8A (38 mg, 0.0643 mmol) in THF (0.4 mL). The mixture was stirred at 50 °C for 16 h. EtOAc (5 mL) and water (2 mL) were added to the mixture. The organic layer was separated, dried over NaSO, filtered, concentrated in vacuo, and triturated from MeCN (1 mL) to give 2707 (21 mg, 67%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 4.02 (q, J = 8.0 Hz, 1H), 3.94-3.85 (m, 1H), 3.69 (d, J = 9.2 Hz, 1H), 3.54 (d, J = 9.2 Hz, 1H), 2.10-1.59 (m, 13H), 1.55-0.99 (m, 17H), 0.98-0.88 (m, 4H), 0.85 (s, 3H), 0.75-0.62 (m, 4H). HPLC Rt=3.93 min (8.0 min chromatography), 50-100_AB_E, 100% purity. MS C 28 H 44 F3O2[M+H-H2O] + MS ESI calculated value 469.3288, found value 469.3244. Example 28: Synthesis of E-2817 [ka]

[0426] The synthesis of ST-200-CF3_6C can be found in Example 5.

[0427] Synthesis of ST-200-43-4_2 [ka] To a suspension of t-BuOK (3.53 g, 31.6 mmol) in THF (30 mL) was added MeSI (4.18 g, 20.5 mmol) under N at 15 °C. The suspension was stirred at 15 °C for 30 min. To this mixture was added a solution of 200-DA-E31_1A (2 g, 15.8 mmol) in 10 mL of THF dropwise at 15 °C. The mixture was stirred at 15 °C for 16 h. The mixture was quenched with saturated NH4Cl (100 mL) and extracted with EtOAc (3 × 150 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to give 200-DA-E31_1 (1.8 g, 81%) as a liquid. 1 H NMR (400 MHz, CDCl3) δ 2.58 (s, 2H), 1.90-1.80 (m, 1H), 1.70-1.55 (m, 2H), 1.54-1.45 (m, 3H), 1.40-1.30 (m, 2H), 1.00-0.90 (m, 6H).

[0428] Synthesis of ST-200-3CF3-A18_1 [ka] First, n-BuLi (0.5 mL, 2.5 M in hexane, 1.25 mmol) was added to THF (0.5 mL). A solution of ST-200-CF3_6C (250 mg, 0.4746 mmol) in THF (3 mL) was added at −70° C. The mixture was stirred at −70° C. for 1 h. ST-200-43-4_2 (133 mg, 0.9492 mmol) was added at −70° C. The mixture was stirred at −70° C. for another 1 h. The mixture was warmed to 25° C. and stirred for 16 h. The reaction mixture was quenched by adding NH4Cl (50 mL, saturated aqueous solution) and extracted with EtOAc (2 × 30 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated to give ST-200-3CF3-A18_1 (390 mg, crude) as a solid, which was used directly in the next step .

[0429] Synthesis of E-2817 [ka] A solution of ST-200-3CF3-A18_1 (390 mg, 0.5847 mmol) in MeOH (25 mL) was heated at 60 °C. Mg powder (500 mg, 20.8 mmol) was added in four portions at 60 °C. The mixture was stirred at 60 °C for 1 h. The mixture was quenched with HCl (50 mL, 2 M) until the reaction became clear and extracted with DCM (2 × 50 mL). The combined organic phases were dried over Na2SO4, filtered, concentrated, and purified by flash column (0–10% EtOAc in PE) to give 135 mg of a solid. The impure product was purified by flash column (0–20% EtOAc in PE) to give E-2817 (101 mg, 75%) as a solid. 1H NMR (CDCl3, 400MHz) δ 2.08-2.03 (m, 1H), 1.98-1.88 (m, 2H), 1.78-1.73 (m, 2H), 1.73-1.60 (m, 3H), 1.60-1.45 (m, 12H), 1.45-1.27 (m, 7H), 1.27-1.19 (m, 9H), 1.19-1.00 (m, 6H), 0.93-0.84 (m, 9H), 0.75-0.64 (s, 4H). LCMS Rt=1.463 min (2 min chromatography), 30-90AB, 100% purity, C 32 H 52 FO[M+H-HO] + MS ESI calculated value 509, measured value 509. Example 29: Synthesis of 2918 [ka]

[0430] The synthesis of ST-200-CF3_6C can be found in Example 5.

[0431] Synthesis of ST-200-3CF3-A8_1 [ka] A suspension of ST-200-CF3_6C (250 mg, 0.475 mmol) in THF (2.5 mL) was added dropwise to a solution of n-BuLi (568 μL, 2.5 M in hexane, 1.42 mmol) in THF (0.5 mL) under N2 at −78 °C. The mixture was stirred at −78 °C for 30 min. 2-(trifluoromethyl)oxirane (79.7 mmol) was added. g, 0.712 mmol) was added dropwise at −78° C. The mixture was stirred for an additional 30 min and then gradually warmed to 25° C. The reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl (30 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give ST-200-3CF3-A8_1 (340 mg, crude) as a solid, which was used directly in the next step.

[0432] Synthesis of 2918 [ka] A solution of ST-200-3CF3-A8_1 (340 mg, 0.5322 mmol) in MeOH (25 mL) was heated at 60 °C. Mg powder (508 mg, 21.2 mmol) was added in four portions at 60 °C. The mixture was stirred at 60 °C for 1 h. The mixture was quenched with HCl (50 mL, 1 N) until the reaction became clear and extracted with DCM (2 × 30 mL). The combined organic phases were dried over Na2SO4, filtered, concentrated, and purified by flash column (0–10% EtOAc in PE) to give 63 mg of a solid, which was triturated from DCM and hexane to give 2918 (5 mg, 2%). 1 H NMR (CDCl3,400MHz) δ 3.90-3.80 (m, 1H), 2.20-1.70 (m, 6H), 1.70-1.50 (m, 7H), 1.50-1.25 (m, 5H), 1.25-1.10 (m, 5H), 1.10-0.80 (m, 12H), 0.70-0.65 (m, 4H). LCMS Rt=1.219 min (2 min chromatography), 30-90AB, 100% purity. Example 30: Synthesis of 3035 [ka]

[0433] Experimental work on intermediate ST-200-CF3_4A can be found in Example 3.

[0434] Synthesis of tosylates: [ka] To a suspension of LiAlH4 (45.3 g, 1.26 mol) in THF (1 L) was added dropwise a solution of 7330_3S (100 g, 632 mmol) in THF (500 mL) at 0 °C, and the internal temperature was allowed to rise to about 50 °C. After addition, the mixture was stirred at 70 °C for 16 h. The mixture was quenched with HCl (1 L, 3 M aqueous solution) to pH = 2, and then The resulting mixture was extracted with MTBE (3×500 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure (<40 °C) to afford 7330_4S (92 g, crude) as an oil. 1 H NMR (400 MHz, CDCl3) δ 3.96-3.92 (m, 1H), 3.58-3.53 (m, 1H), 3.08 (s, 1H), 1.98-1.89 (m, 1H), 1.38 (s, 3H). To a solution of 7330_4S (50 g, 346 mmol) in pyridine (300 mL) was added 4-methylbenzene-1-sulfonyl chloride (98.9 g, 519 mmol) portionwise over 5 min at 0 °C. The reaction solution was stirred at 20 °C for 16 h. The reaction mixture was quenched with 2 N HCl (400 mL) to pH = 1-2 at 0 °C. The internal temperature was maintained below 30 °C, and the mixture was extracted with MTBE (3 × 200 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified by column chromatography (0-10% EtOAc in PE) to give 7330_5S (93 g, 90%, 99.42% ee) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 7.6 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 4.13-4.03 (m, 2H), 2.99 (s, 1H), 2.46 (s, 3H), 1.37 (s, 3H), LCMS Rt=1.103 min (2.0 min chromatography), 10-80AB, 100% purity, MS not detected.

[0435] Synthesis of ST-200-3CF3-C11S_1 [ka] A suspension of ST-200-CF3_4A (250 mg, 0.48 mmol) in THF (4 mL) was added dropwise to a solution of n-BuLi (0.48 mL, 2.5 M in hexane, 1.19 mmol) in THF (1 mL) at −70°C under N2. After stirring at −70°C for 30 min, diisopropylamine (120 mg, 1.19 mmol) was added dropwise at −70°C, followed by (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropyl 4-methylbenzenesulfonate (212 mg, 0.71 mmol) at −70°C. The mixture was stirred for an additional 30 min and then gradually warmed to 25°C. The reaction mixture was stirred at 25°C for 24 h. The reaction mixture was quenched with saturated aqueous NH4Cl (5 mL) and extracted with EtOAc (3 × 10 mL). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give ST-200-3CF3-C11S_1 (480 mg, crude), which was used directly.

[0436] Synthesis of 3035 [ka] Mg powder (705 mg, 29.4 mmol) and NiCl (1 mg, 0.007 mmol) were added to a solution of ST-200-3CF-C11S (480 mg, 0.74 mmol) in 50 mL of anhydrous MeOH at 60 °C with stirring under N. The reaction mixture was quenched with 2 M HCl (10 mL) until the solid dissolved. The mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with saturated NaHCO (50 mL), brine (50 mL), dried over NaSO, filtered, and concentrated. The residue was purified by flash column (0–20% EtOAc in PE) to give the crude product, which was further purified by recrystallization from MeCN (10 mL) at 85 °C to give 3035 (53 mg, 21%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 5.41-5.34 (m, 1H), 2.53-2.46 (s, 2H), 2.08-1.92 (m, 4H), 1.91-1.58 (m, 7H), 1.54-1.35 (m, 7H), 1.33-1.30 (s, 3H), 1.29-1.08 (m, 5H), 1.07-1.05 (s, 3H), 1.05-0.91 (m, 5), 0.73-0.63 (s, 3). LCMS R t =1.213 min (2 min chromatography), 30-90AB_2MIN_E, purity 99%. Example 31: Synthesis of 3149 [ka]

[0437] Experimental work on intermediate ST-200-CF3_4A can be found in Example 3.

[0438] Synthesis of ST-200-3CF3_C8R_1 [ka] A suspension of ST-200-CF3_4A (250 mg, 0.476 mmol) in THF (2.5 mL) was added dropwise to a solution of n-BuLi (0.568 mL, 2.5 M in hexane, 1.42 mmol) in THF (0.5 mL) under N2 at -65 °C. Diisopropylamine (143 mg, 1.42 mmol) was added and after stirring at -65 °C for 30 min, a solution of (R)-2-(trifluoromethyl)oxirane (63.9 mg, 0.571 mmol) was added dropwise at -65 °C. The mixture was stirred for an additional 30 min and then gradually warmed to 25 °C. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl (30 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give ST-200-3CF3-C8R_1 (250 mg, crude) as a solid, which was used directly in the next step.

[0439] Synthesis of 3149 [ka] Mg powder (379 mg, 15.6 mmol) was added to a solution of ST-200-3CF3-C8R_1 (250 mg, 0.392 mmol) and nickel(II) chloride (12.7 mg, 0.098 mmol) in dry methanol (50 mL) under N2 at 50 °C. The mixture was stirred while Mg was added, and continuous hydrogen evolution began. The reaction mixture was then stirred at 60 °C for 1 h. The reaction mixture was quenched with 2 M HCl (100 mL), which was added dropwise at 10 °C until the solids dissolved. After extraction with EtOAc (2 × 150 mL), the combined organic layers were washed with saturated aqueous NaHCO (300 mL), brine (300 mL), dried over Na SO , filtered, and concentrated in vacuo to give a solid, which was purified by silica gel chromatography (PE / THF = 4 / 1) to give the crude product, which was recrystallized from MeCN (10 mL) to give impure product (30 mg, 15%). The impure product (30 mg, 0.068 mmol) was purified by SFC (column: AD 250 mm * 30 mm, 10 μm), gradient: 20-20% B (A = 0.1% NH / HO, B = EtOH), flow rate: 60 mL / min) to give 3149 (12 mg, 40%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 5.40-5.35 (m, 1H), 3.75-3.65 (m, 1H), 2.50-2.45 (m, 2H), 2.10-1.70 (m, 11H), 1.69-1.50 (m, 10H), 1.49-0.90 (m, 10H), 0.69 (s, 3H). HPLC Rt=6.25 min (1.2 min chromatography), 30-90AB, purity 98%. 26 H 39 F6O2[M+H] - HRMS ESI calculated value 497.2849, found value 497.2842. Example 32: Synthesis of 3266 [ka]

[0440] Experimental work on intermediate ST-200-CF3_4A can be found in Example 3.

[0441] Synthesis of ST-200-3CF3-C7R_1 [ka] A suspension of ST-200-CF3_4A (250 mg, 0.476 mmol) in THF (4 mL) was added dropwise to a solution of n-BuLi (568 mL, 2.5 M in hexane, 1.42 mmol) in THF (1 mL) under N2 at −65 °C. After stirring at −65 °C for 30 min, diisopropylamine (143 mg, 1.42 mmol) was added at −65 °C. Then, (R)-2-methyloxirane (82.4 mg, 1.42 mmol) was added dropwise at −65 °C. The mixture was stirred for an additional 30 min and then gradually warmed to 25 °C. The reaction mixture was stirred at 25 °C for 16 h. The reaction was quenched with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the crude product as a solid, which was used directly in the next step.

[0442] Synthesis of 3266 [ka] Mg powder (410 mg, 17.1 mmol) was added in four portions to a solution of ST-200-3CF3_C7R_1 (250 mg, 0.428 mmol) and NiCl2 (5.52 mg, 0.043 mmol) in dry methanol (20 mL) at 50 °C with stirring under N2. After stirring at 60 °C for 1 h, the mixture was quenched with HCl (50 mL, 1N) until the reaction became clear and extracted with EtOAc (3 × 30 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column (0–15% EtOAc in PE) to give the impure product (100 mg, 0.225 mmol, impure, containing 13% of the 22,23 alkene). Lindlar's catalyst (200 mg, 0.225 mmol) was added to a solution of the impure product in THF (20 mL) under N2. The mixture was degassed under vacuum and purged with H2 several times. The mixture was stirred at 25 °C for 2 h. The reaction mixture was filtered through a Celite pad and washed with THF (3 × 10 mL). The filtrate was concentrated to give the impure product, which was triturated with n-hexane (10 mL) at 68 °C for 2 h to give the impure product as a solid. The impure product was purified by silica gel chromatography (PE / EtOAc = 0 to 5 / 1) to give 3266 (48 mg, impure) as a solid, which was purified by SFC (column: AD (150 × 4.6 mm, 3 μm), gradient: 5% to 40% B (A: CO2 B: ethanol), flow rate: 2.5 mL / min) to give 3266 (10 mg) as a solid. 1 H NMR (400 MHz, CDCl3) δ 5.40-5.33. (m, 4H), 1.23-0.75 (m, 16H), 0.68 (s, 3H). LCMS Rt=1.149 min (2.0 min chromatography), 30-90AB, 100% purity, C 26 H 40 FO[M+H-HO] +MS ESI calculated value 425, measured value 425. Example 33: Synthesis of 3382 [ka]

[0443] The stereochemistry was assigned based on synthesis with a chiral epoxide (see Example 35 for synthesis).

[0444] Experimental work on intermediate ST-200-CF3_4A can be found in Example 3.

[0445] Synthesis of ST-200-31-6_1 [ka] A suspension of ST-200-CF3-4A (500 mg, 0.95 mmol) in THF (4 mL) was added dropwise to a solution of n-BuLi (0.95 mL, 2.5 M in hexane, 2.38 mmol) in THF (1 mL) at −70° C. under N. After stirring at −70° C. for 30 min, a solution of diisopropylamine (240 mg, 2.38 mmol) was added dropwise at −70° C., followed by a solution of 2-(tert-butyl)oxirane (142 mg, 1.42 mmol) at −70° C. The mixture was stirred at −70° C. for an additional 30 min and then gradually warmed to 25° C. After stirring at 25° C. for 24 h, the reaction mixture was quenched with saturated aqueous NH4Cl (5 mL) and extracted with EtOAc (3×20 mL). The combined organic phase was washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give ST-200-31-6_1 (650 mg, crude), which was used directly.

[0446] Synthesis of ST-200-31-6 [ka] Mg powder (998 mg, 41.6 mmol) and NiCl (5 mg, 0.05 mmol) were added to a solution of ST-200-31-6 (650 mg, 1.04 mmol) in 100 mL of anhydrous MeOH at 60 °C with stirring under N. The reaction mixture was quenched with 2 M HCl (50 mL) until the solid dissolved. The mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with saturated NaHCO (150 mL), brine (150 mL), dried over NaSO, filtered, and concentrated. The residue was purified by flash column (0–15% EtOAc in PE) to give impure ST-200-31-6 as a solid. Lindlar catalyst (200 mg) was added to a solution of ST-200-31-6 in EtOAc (10 mL) under N. The suspension was degassed under vacuum and purged with H2 three times. The solution was then hydrogenated under 15 psi of hydrogen at 25 °C for 4 hours. The mixture was filtered through a pad of Celite and washed with EtOAc (3 x 10 mL). The filtrate was concentrated and concentrated to give ST-200-31-6 (210 mg, 43%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 5.39-5.34 (m, 1H), 3.18-3.06 (m, 1H), 2.49 (s, 2H), 2.17 (s, 1H), 2.02-1.58 (m, 7H), 1.53-1.29 (m, 9H), 1.22-0.97 (m, 10H), 0.95-0.84 (m, 13H), 0.72-0.65 (m, 3H).

[0447] Synthesis of 3382 [ka] ST-200-31-6 (210 mg, 0.43 mmol) was purified by SFC (column: AD (250 mm * 30 mm, 10 μm)), gradient: 20-20% B (A = 0.1% NH3 / HO, B = EtOH), flow rate: 50 mL / min) to give 3382 (90 mg, 43%) as a solid. 1H NMR (400 MHz, CDCl3) δ 5.42-5.34 (m, 1H), 3.19-3.12 (m, 1H), 2.48 (s, 2H), 2.09-1.67 (m, 8H), 1.53-1.23 (m, 12H), 1.22-0.98 (m, 8H), 0.95-0.84 (m, 12H), 0.69 (s, 3H). LCMS Rt=1.440 min (2 min chromatography), 30-90AB_2MIN_E, purity 100%, C 29 H 46 FO[M+H-HO] + MS ESI calculated value 467, observed value 467. SFC_E1 Rt=4.337 min (10 min chromatography), AD_3_EtOH_DEA_5_40_25ML, purity: 100%. Example 34: Synthesis of 3495 and 3496 [ka]

[0448] X-ray data assigned the stereochemistry of 3496. Experimental studies of intermediate ST-200-CF3_4A can be found in Example 3.

[0449] Synthesis of 200-DA-C24_8_2 [ka] Sodium hydride (5.98 g, 60% in mineral oil, 150 mmol) was added portionwise to a mixture of trimethylsulfonium iodide (30.6 g, 150 mmol) in THF (100 mL) under N at 0 °C. The mixture was stirred at 0 °C for 30 min. Dihydrofuran-3(2H)-one (10 g, 116 mmol) in DMSO (100 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The mixture was poured portionwise into ice water (500 mL) and extracted with DCM (2 × 500 mL). The combined organic phases were washed with brine (500 mL), dried over Na SO , filtered, and concentrated to give 200-DA-C24_8_2 (4 g, crude, 34%) as an oil at 18 °C, which was used directly in the next step.

[0450] Synthesis of ST-200-CF3_8 [ka] Butyllithium (2.71 mL, 2.5 M in n-hexane, 6.79 mmol) was added to a solution of diisopropylamine (714 mg, 7.33 mmol) in THF (3 mL) at −70° C. The mixture was warmed to 0° C. and stirred at 0° C. for 30 min. The mixture was cooled to −70° C., and 200-DA-C24_8_2 (300 mg, 2.99 mmol) in THF (2 mL) was added. The mixture was stirred at −70° C. for 1 h. ST-200-CF3_4A (1.42 g, 2.71 mmol) in THF (2 mL) was added at −70° C. The mixture was warmed to 25° C. and stirred at this temperature for 16 h. The mixture was quenched with saturated NH4Cl (10 mL). The mixture was extracted with EtOAc (2 × 10 mL). The organic phase was washed with brine (2 × 10 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (0 to 50% EtOAc in PE) to give ST-200-CF3_8 (280 mg, 17%) as a solid, which was used directly in the next step.

[0451] Synthesis of compound 10 [ka] Nickel(II) chloride (580 μg, 4.48 μmol) and Mg powder (435 mg, 17.9 mmol) were added in four portions to a solution of ST-200-CF3_8 (280 mg, 0.448 mmol) in 50 mL of dry methanol at 60 °C under N2. The reaction mixture was quenched with 1 M HCl (150 mL), which was added dropwise until the solid dissolved. After extraction with EtOAc (3 × 50 mL), the organic layer was washed with saturated NaHCO3 (50 mL), brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (0–20% EtOAc in PE) to give compound 10 (210 mg, 97%) as a solid. 1 H NMR CDCl3400MHz δ 5.39-5.35 (m, 1H), 3.93-3.82 (m, 1H), 3.72-3.68 (m, 1H), 3.59-3.51 (m, 1H), 2.49 (s, 2H), 2.10-1.80 (m, 8H), 1.80-1.62 (m, 4H), 1.60-1.39 (m, 7H), 1.39-1.12 (m, 6H), 1.12-0.91 (m, 9H), 0.69 (s, 3H).

[0452] Synthesis of 3495 and 3496 [ka] 10 (280 mg, 0.577 mmol) was purified by SFC (column: AS (250 mm * 30 mm, 5 μm), gradient: 20-20% B (A = 0.1% NH3 / HO, B = EtOH), flow rate: 60 mL / min) to give 3495 (20 mg, 7%) as a solid and 3496 (32 mg, 11%) as a solid. 3495 1H NMR CDCl3400MHz δ 5.39-5.35 (m, 1H), 4.05-3.98 (m, 1H), 3.93-3.85 (m, 1H), 3.72-3.68 (m, 2H), 3.59-3.51 (m, 1H), 2.49 (s, 2H), 2.05-1.72 (m, 9H), 1.55-1.40 (m, 7H), 1.72-1.40 (m, 7H), 1.40-0.90 (m, 9H), 0.69 (s, 3H). LCMS Rt=1.081 min (2.0 min chromatography), 30-90AB_2MIN_E.M, purity 100%, C 28 H 42 F3O2[M+H-H2O] + MS ESI calculated value 467, observed value 467. 3496 1 H NMR CDCl3400MHz δ 5.39-5.35 (m, 1H), 4.05-3.98 (m, 1H), 3.90-3.85 (m, 1H), 3.72-3.68 (m, 1H), 3.59-3.51 (m, 1H), 2.49 (s, 2H), 2.05-1.72 (m, 10H), 1.68-1.1.60 (m, 2H), 1.52-1.25 (m, 8H), 1.25-0.92 (m, 13H), 0.69 (s, 3H). LCMS Rt=1.095 min (2.0 min chromatography), 30-90AB_2MIN_E.M, purity 100%, C 28 H 42 F3O2[M+H-H2O] + MS ESI calculated value 467, observed value 467. Example 35: Synthesis of 3507 [ka]

[0453] The stereochemistry was assigned based on synthesis via chiral epoxides.

[0454] Experimentation with intermediate ST-200-31-6 can be found in Example 33.

[0455] Synthesis of ST-200-31-5 [ka] ST-200-31-6 (210 mg, 0.43 mmol) was purified by SFC (column: AD (250 mm * 30 mm, 10 um)), gradient: 20-20% B (A = 0.1% NH3 / HO, B = EtOH), flow rate: 50 mL / min to give impure 3507 (100 mg, 45%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 5.42-5.33 (m, 1H), 3.15-3.06 (m, 1H), 2.4 8 (s, 2H), 2.08-1.92 (m, 4H), 1.89-1.57 (m, 6H), 1.53-1.23 (m, 8H), 1.21-0.97 (m, 10H), 0.96-0.83 (m, 12H), 0.68 (s, 3H).

[0456] Synthesis of 3507 [ka] Lindlar catalyst (100 mg) was added to a solution of an impure sample (100 mg, 0.21 mmol, containing the 22,23-olefin) in 5 mL of EtOAc under N. The suspension was degassed under vacuum and purged with H three times. The solution was then hydrogenated under 15 psi of hydrogen at 25 °C for 4 h. The mixture was filtered through a pad of Celite and washed with 3 × 10 mL of EtOAc. The filtrate was concentrated to give a solid. 1H NMR showed that 12.5% ​​of the 22,23-olefin was still present. Impure 3507 was dissolved in THF / MeOH (3 / 3 mL) and treated with Lindlar (100 mg) under N. The suspension was degassed under vacuum and purged with H three times. The solution was then hydrogenated under 15 psi of hydrogen at 25 °C for 4 h. The mixture was filtered through a pad of Celite and washed with THF (3 × 10 mL). The filtrate was concentrated and triturated with PE (5 mL) to give 3507 as a solid, which was triturated with n-hexane (5 mL) at 25 °C to give 3507 (40 mg, 40%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 5.42-5.34 (m, 1H), 3.13-3.06 (m, 1H), 2.48 (s, 2H), 2.09-1.94 (m, 4H), 1.89-1.57 (m, 6H), 1.54-1.34 (m, 6H), 1.32-1.08 (m, 5H), 1.07-0.97 (m, 7H), 0.94 (d, J = 6.4 Hz, 3H), 0.89 (s, 9H), 0.68 (s, 3H). LCMS Rt=1.298 min (2 min chromatography), 30-90AB_2MIN_E, purity 100%, C 29 H 46 FO[M+H-HO] + MS ESI calculated value 467, observed value 467. SFC_E1 Rt=3.887 min (10 min chromatography), AD_3_EtOH_DEA_5_40_25ML, 100% de. Synthesis confirming the stereochemistry of 3507 and 3634 [ka] To a solution of THF (0.5 mL) was added n-BuLi (0.8 mL, 2.5 M in hexane, 2 mmol) and a solution of DD (420 mg, 0.8 mmol) in THF (2 mL) at −70° C. After stirring at −70° C. for 1 h, (R)- 2-(tert-Butyl)oxirane (120 mg, 1.2 mmol) was added at −70° C. The mixture was stirred at −70° C. for an additional 1 h, then warmed to 25° C. and stirred for 16 h. The reaction mixture was quenched with saturated NH4Cl (10 mL) and extracted with EtOAc (2 × 5 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated. The residue (400 mg) was used directly in the next step. To a mixture of DDA (400 mg, crude) in MeOH (30 mL) was added NiCl (8.29 mg, 0.64 mmol) at 25 °C. The mixture was then warmed to 60 °C, and Mg powder (671 mg, 25.5 mmol) was added in three portions. The reaction was quenched with HCl (1 M, 10 mL), and the mixture was extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated. The residue was purified by flash combi (0-30% EtOAc in PE) to give 3507 (110 mg, impure) as a solid, which was further purified by SFC (column: AD (250 mm * 30 mm, 10 um)), gradient: 30-30% B (A = 0.1% NH3 / HO IPA, B = EtOH), flow rate: 50 mL / min) to give 3507 (100 mg) as a solid. 1 H NMR (400 MHz, CDCl3) δ 5.40-5.34 (m, 1H), 3.14-3.02 (m, 1H), 2.48 (s, 2H), 2.10-1.91 (m, 3H), 1.90-1.69 (m, 4H), 1.69-1.51 (m, 6H), 1.51-1.27 (m, 7H), 1.22-0.98 (m, 8H), 0.98-0.92 (m, 3H), 0.89 (s, 9H), 0.68 (s, 3H). LCMS Rt=1.322 min (2 min chromatography), 30-90AB_2MIN_E, purity 100%, C 29 H 46 FO[M+H-HO] + MS ESI calculated value 467, observed value 467. SFC Rt=3.804 min (10 min chromatography), AD_3_EtOH_DEA_5_40_25ML, 100% de. To a solution of 3507 (70 mg) in THF (10 mL) was added Pd(OH) / C (20%, dry, 100 mg). The mixture was stirred under H (50 psi) at 50 °C for 18 h. The mixture was filtered and concentrated in vacuo. The residue was purified by flash combi (0-15% EtOAc in PE) to give 3634 (13 mg, 19%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 3.17-2.98 (m, 1H), 2.14-1.78 (m, 4H), 1.78-1.60 (m, 6H), 1.57-1.34 (m, 7H), 1.34-1.00 (m, 13H), 0.98 (s, 3H), 0.92 (m, 3H), 0.89 (s, 9H), 0.65 (s, 3H). LCMS Rt=1.349 min (2.0 min chromatography), 30-90_AB_E, 100% purity, no MS signal. MS C 29 H 48 FO[M+H-HO] + MS ESI calculated value 469, observed value 469. Example 36: Synthesis of 3634 [ka]

[0457] The experimental procedure for intermediate 3507 can be found in Example 3.

[0458] Synthesis of 3634 [ka] To a solution of 3507 (70 mg) in THF (10 mL) was added Pd(OH) / C (20%, dry, 100 mg). The mixture was stirred under H (50 psi) at 50 °C for 18 h. The mixture was filtered and concentrated in vacuo. The residue was purified by flash combi (0-15% EtOAc in PE) to give 3634 (13 mg, 19%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 3.17-2.98 (m, 1H), 2.14-1.78 (m, 4H), 1.78-1.60 (m, 6H), 1.57-1.34 (m, 7H), 1.34-1.00 (m, 13H), 0.98 (s, 3H), 0.92 (m, 3H), 0.89 (s, 9H), 0.65 (s, 3H). LCMS Rt=1.349 min (2.0 min chromatography), 30-90_AB_E, 100% purity, no MS signal. MS C 29 H 48 FO[M+H-HO] + MS ESI calculated value 469, observed value 469. Example 37: Synthesis of 3788 [ka]

[0459] Experimentation with intermediate ST-200-31-4 can be found in Example 33.

[0460] Synthesis of 3788 [ka] Pd(OH)2 / C (100 mg) was added to a solution of ST-200-31-4 (60 mg, 0.12 mmol) in THF / MeOH (5 mL / 5 mL), and the mixture was degassed and backfilled with H2 three times. The reaction was then stirred at 50 °C under 50 psi of H2 for 16 h. The reaction mixture was filtered through a pad of Celite and washed with EtOAc (100 mL). The filtrate was concentrated to give impure ST-200-31-3B as a solid. To a solution of impure ST-200-31-4 in THF / MeOH (3 mL / 3 mL), Pd(OH)2 / C (50 mg) was added, and the mixture was degassed and backfilled with H2 three times. The reaction was then stirred at 50 °C under 50 psi of H2 for 72 h. The reaction mixture was filtered through a pad of Celite and washed with EtOAc (100 mL). The filtrate was concentrated to give 40 mg of crude product, which was triturated with n-hexane (2×3 mL) to give 3788 (7 mg, 17%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 3.19-3.08 (m, 1H), 2.13-1.81 (m, 4H), 1.77-1.58 (m, 4H), 1.54-1.35 (m, 9H), 1.34-1.01 (m, 13H), 1.01-0.96 (m, 3H), 0.94-0.86 (m, 12H), 0.66 (s, 3H). LCMS Rt=1.313 min (2.0 min chromatography), 30-90AB_2MIN_E, purity 98%, C 29 H 48 FO[M+H-HO] + MS ESI calculated value 469, observed value 469. Example 38: Synthesis of 3877 and 3886 [ka]

[0461] The stereochemistry of 3877 is shown below; assigned by NMR.

[0462] Synthesis of ST-200-74-5_1 [ka] Me3SI (4.71 g, 23.1 mmol) was added to a suspension of t-BuOK (3.98 g, 35.6 mmol) in THF (40 mL) under N2 at 35 °C. After stirring at 35 °C for 30 min, a solution of ST-200-74-5_1 (2 g, 17.8 mmol) was added dropwise at 35 °C. The mixture was stirred at 35 °C for 16 h, quenched with saturated NH4Cl (50 mL), and extracted with EtOAc (3 × 50 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo to give ST-200-74-5_2 (1.8 g, crude) as a liquid, which was used directly in the next step.

[0463] Synthesis of ST-200-74-5_3 [ka] n-BuLi (0.948 mL, 2.5 M in hexane, 2.37 mmol) was added to THF (5 mL). A solution of ST-200-CF3_6C (500 mg, 0.949 mmol) in THF (15 mL) was added at -70 °C. After stirring at -70 °C for 1 h, 6-methyl-1-oxaspiro[2.5]octane (358 mg, 2.84 mmol) was added to the mixture. The mixture was added at 70°C. The mixture was stirred at -70°C for an additional 1 h, then warmed to 15°C and stirred for 16 h. After quenching with NH4Cl (50 mL), the mixture was extracted with EtOAc (2 x 30 mL). The organic layer was separated, dried over Na2SO4, filtered, concentrated, and purified by Combiflash (0-20% EtOAc in PE) to give ST-200-74-5_3 (350 mg, crude) as a solid, which was used directly in the next step.

[0464] Synthesis of 3877 [ka] A solution of ST-200-74-5_3 (350 mg, 0.536 mmol) in MeOH (30 mL) was heated at 65 °C. Mg powder (513 mg, 21.4 mmol) was added in one portion at 65 °C. The mixture was refluxed at 65 °C for 1 h. The mixture was quenched with HCl (40 mL, 2 N) until the reaction was clear and extracted with DCM (2 × 30 mL). The combined organic layers were dried over NaSO, filtered, concentrated, and purified by silica gel chromatography (0–12% EtOAc in PE) to give 3877 (12 mg, 4%) as a solid. 3877: 1 H NMR (400 MHz, CDCl3) δ 2.11-1.90 (m, 3H), 1.89-1.74 (m, 2H), 1.73-1.58 (m, 5H), 1.53-1.43 (m, 6H), 1.42-1.19 (m, 14H), 1.18-0.96 (m, 7H), 0.96-0.80 (m, 10H), 0.74-0.60 (m, 4H). LCMS Rt=1.728 min (2 min chromatography), 30-90AB_2MIN_E, 100% purity. MS ESI scan (2.939-3.092 min, 10 scans) Frag = 50.0 V, 80-100_1_4min.m, C 31 H 51 F3O2Na[M+Na] + MS ESI calculated value 535, measured value 535. [ka]

[0465] Synthesis of ST-200-096-011A / B [ka] To a solution of ST-200-74-5_3 (700 mg, 1.07 mmol) in MeOH (40 mL) was added NiCl (27.6 mg, 0.214 mmol) and Mg powder (1.02 g, 41.8 mmol) in one portion at 65 °C. The mixture was stirred at 65 °C for 10 min. Another portion of Mg powder (513 mg, 22.3 mmol) was added in one portion. After stirring at 65 °C for 10 min, the mixture was quenched with HCl (200 mL, 1 N) and extracted with EtOAc (3 × 50 mL). The combined organic phases were dried over Na2SO4, filtered, concentrated, and purified by Combiflash (0-15% EtOAc in PE) to give ST-200-096-011A (63 mg, 11%, peak 1) and ST-200-096-011B (114 mg, 20%, peak 2) as solids. 3877 1 H NMR (400 MHz, CDCl3) δ 2.09-1.93 (m, 3H), 1.90-1.76 (m, 2H), 1.73-1.57 (m, 8H), 1.51-1.34 (m, 8H), 1.33-1.18 (m, 6H), 1.17-0.98 (m, 8H), 0.97-0.87 (m, 7H), 0.84 (s, 3H), 0.73-0.63 (m, 4H). LCMS Rt=1.391 min (2 min chromatography), 30-90AB_2MIN_E, 100% purity. MS ESI scan (1.955-2.16 min, 8 scans) Frag = 50.0 V, 80-100 1 4 min.m, C 31 H 51 F3O2Na[M+Na] + MS ESI calculated value 535, measured value 535. 1H NMR (400 MHz, CDCl3) δ 2.09-2.00 (m, 2H), 1.99-1.89 (m, 1H), 1.87-1.76 (m, 2H), 1.71-1.61 (m, 3H), 1.55-0.42 (m, 10H), 1.41-1.19 (m, 13H), 1.14-0.96 (m, 6H), 0.95-0.86 (m, 7H), 0.84 (s, 3H), 0.72-0.62 (m, 4H). LCMS Rt=1.450 min (2 min chromatography), 30-90AB_2MIN_E, 100% purity. MS ESI scan (1.938-2.617 min, 9 scans) Frag = 50.0 V, 80-100 1 4 min.m, C 31 H 51 F3O2Na[M+Na] + MS ESI calculated value 535, measured value 535. Example 39: Synthesis of 3983 [ka]

[0466] See Example 5 for the synthesis of ST-200-CF3_6C.

[0467] Synthesis of ST-310-15-2_2 [ka] A solution of Me3SI (13.6 g, 66.7 mmol) and t-BuOK (17.8 mL, 5 M in THF, 89.0 mmol) in DMSO (100 mL) was stirred and heated at 25 °C for 30 min under N2. Cycloheptanone (5 g, 44.5 mmol) was added to the reaction mixture and stirred at 25 °C for 3 h. The reaction was treated with water (300 mL) and extracted with EtOAc (2 × 100 mL). The combined organic phase was washed with water (2 × 300 mL), brine (2 × 300 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give ST-200-74-5_2 (4 g, 71%) as a liquid. 1 H NMR (400 MHz, CDCl3) δ 2.59 (s, 2H), 1.72-1.50 (m, 12H).

[0468] Synthesis of ST-310-15-2_3 [ka] n-BuLi (0.568 mL, 1.42 mmol, 2.5 M in hexane) was added to a solution of ST-200-CF3_6C (300 mg, 0.569 mmol) in THF (3 mL) at −70 °C under N2. After cooling to −70 °C, 1-oxaspiro[2.6]nonane (107 mg, 0.853 mmol) was added. The reaction was warmed to 25 °C and stirred at 25 °C for 12 h. The reaction was quenched with NH4Cl (10 mL, saturated aqueous solution), water (50 mL), and extracted with EtOAc (3 × 10 mL). The combined organic phases were concentrated to give a residue, which was purified by silica gel chromatograp...

Claims

[Claim 1] The invention described in the specification.

Images