Oxosterols and methods of use thereof

Abstract

The invention relates to an oxysterol and a use method thereof. Provided are compounds according to Formula (I), and pharmaceutically acceptable salts and pharmaceutical compositions thereof; wherein R2, R3, R4, R5 and R6 are as defined herein. The compounds of the invention are contemplated to be useful in the prevention and treatment of a variety of conditions. # imgabs0 #

Description

[0001] This application is a divisional application of the Chinese invention patent application (application date: October 18, 2017; application number: 202210676312.9; invention name: Oxysterols and methods of use thereof).

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application No. 62 / 409,761, filed on October 18, 2016, U.S. Provisional Application No. 62 / 409,767, filed on October 18, 2016, U.S. Provisional Application No. 62 / 409,772, filed on October 18, 2016, U.S. Provisional Application No. 62 / 409,774, filed on October 18, 2016, and U.S. Provisional Application No. 62 / 409,764, filed on October 18, 2016, each of which is incorporated herein by reference in its entirety. Background Art

[0004] NMDA receptors are heteromeric complexes composed of NR1, NR2 and / or NR3 subunits and have different recognition sites for exogenous and endogenous ligands. These recognition sites include a binding site for glycine and a binding site for glutamate agonists and modulators. NMDA receptors are expressed in peripheral tissues and the CNS, where they participate in excitatory synaptic transmission. Activation of these receptors contributes to synaptic plasticity in some cases and leads to excitotoxicity in other cases. These receptors are ligand-gated ion channels that allow Ca to flow in upon binding glutamate and glycine. 2+ By, and is important for excitatory neurotransmission and normal CNS function. Positive modulators can be effectively used as therapeutic agents, which have potential clinical uses as cognitive enhancers and for treating mental illnesses in which glutamatergic transmission is reduced or defective (e.g., see Horak et al., J. of Neuroscience, 2004, 24(46), 10318-10325). In contrast, negative modulators can be used as therapeutic agents, which have potential clinical uses for treating mental illnesses in which glutamatergic transmission is pathologically increased (e.g., treating refractory depression).

[0005] Oxysterols are cholesterol analogs that are modulators of NMDA receptor function. New oxysterols are needed that modulate NMDA receptors to prevent and treat conditions associated with NMDA expression and function. Compounds, compositions, and methods described herein are used to achieve these goals. Summary of the Invention

[0006] Provided herein are substituted oxysterols for use in preventing and / or treating a variety of diseases, including but not limited to NMDA-mediated diseases. Also provided are pharmaceutical compositions comprising the compounds of the invention, and methods of use and treatment thereof.

[0007] In one aspect, provided herein are compounds according to formula (I-59):

[0008]

[0009] or a pharmaceutically acceptable salt thereof, wherein: R 2 and R 3 are each independently hydrogen, alkyl (e.g., C1-C6 alkyl), carbocyclic or heterocyclic, or R 2 and R 3 , together with the carbon atoms to which they are attached, form a 3-8 membered ring; R 4 and R 5 are each independently hydrogen, halogen or -OR C , where R C is hydrogen or alkyl (e.g., C1-C6 alkyl), or R 4 and R 5 , together with the carbon atom to which they are attached, form an oxo group; R 6 is absent or is hydrogen; and represents a single bond or a double bond, where When one of them is a double bond, the other is a single bond; when two When both are single bonds, then R 6 is hydrogen; and when When one of them is a double bond, R 6 Does not exist; provided that the following compounds are not included:

[0010]

[0011] In some embodiments, R 2 is hydrogen or alkyl (e.g., C1-C6 alkyl). 2 is a haloalkyl group (eg, a C1-C6 haloalkyl group).

[0012] In some embodiments, R 2 and R 3 Each is independently alkyl (e.g., substituted C1-C6 alkyl) or hydrogen. 2 and R 3 Each is independently unsubstituted alkyl (e.g., unsubstituted C1-C6 alkyl) or hydrogen. 2 and R 3Each is independently C1-C6 haloalkyl (e.g., trifluoromethyl) or hydrogen. In some embodiments, R 2 and R 3 Each is independently hydrogen, carbocyclyl or heterocyclyl. In some embodiments, R 2 and R 3 Each is independently C2-C6 alkyl (e.g., isopropyl or tert-butyl) or hydrogen. 2 and R 3 Each is independently hydrogen or C3-C6 alkyl (eg, isopropyl or tert-butyl).

[0013] In some embodiments, R 2 and R 3 At least one of them is C3-C6 alkyl (e.g., isopropyl or tert-butyl), carbocyclic or heterocyclic; 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, R 2 is isopropyl or tert-butyl and R 3 is methyl or hydrogen. In some embodiments, R 2 is 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 In some embodiments, R 2 is a substituted tert-butyl group and R 3 In some embodiments, R 2 is an unsubstituted tert-butyl group and R 3 In some embodiments, R 2 is trifluoromethyl and R 3 In some embodiments, R 2 is trifluoromethyl and R 3 In some embodiments, R 2 is trifluoromethyl and R 3 In some embodiments, R 2 is trifluoromethyl and R 3 In some embodiments, R 2 is methyl and R 3 In some embodiments, R 2 is a substituted methyl group and R 3 In some embodiments, R 2 is an unsubstituted methyl group and R3 For hydrogen.

[0014] In some embodiments, the 3-8 membered ring is heterogeneous or homogeneous. In some other embodiments, the heterogeneous or homogeneous 3-8 membered ring is substituted with alkyl, haloalkyl, 3-6 membered ring, substituted or unsubstituted alkoxy, or OH.

[0015] In some embodiments, R 4 is -OH or halogen (eg, -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 halogen (e.g., -F). In some embodiments, R 4 and R 5 is halogen (e.g., -F). In some embodiments, R 4 and R 5 For hydrogen.

[0016] In some embodiments, R 2 and R 3 , together with the carbon atoms to which they are attached, form a 5-membered ring. In some embodiments, R 2 is a C2-C6 alkyl group (eg, a substituted or unsubstituted isopropyl group or a substituted or unsubstituted tert-butyl group) and R 3 is C1-C6 alkyl (eg, substituted or unsubstituted C1-C6 alkyl). In some embodiments, R 2 is an unsubstituted C2-C6 alkyl group (eg, an unsubstituted isopropyl group or an unsubstituted tert-butyl group) and R 3 is an unsubstituted C1-C6 alkyl. 2 and R 3 , together with the carbon atom to which they are attached, form a 6-membered ring.

[0017] In some embodiments, R 2 is a carbocyclic or heterocyclic group and R 3 In some embodiments, R 2 and R 3 In some embodiments, R 2 isopropyl and R 3 In some embodiments, R 2 is substituted isopropyl and R 3 In some embodiments, R 2 is substituted isopropyl and R 3 In some embodiments, R 2 and R 3, together with the carbon atoms to which they are attached, form a 3-8 membered carbocyclic (e.g., cyclohexyl) or heterocyclic (e.g., tetrahydrofuranyl or tetrahydropyranyl) ring. In some embodiments, the carbocyclic or heterocyclic ring is substituted (e.g., a ring substituted with 1 or 2 halogen or alkyl groups). In some embodiments, R 2 is cyclobutyl and R 3 In some embodiments, R 2 is tetrahydropyranyl and R 3 For hydrogen.

[0018] In some embodiments, R 2 is a substituted cyclobutyl group and R 3 In some embodiments, R 2 is a substituted tetrahydropyranyl group and R 3 In some embodiments, R 2 is an unsubstituted cyclobutyl group and R 3 In some embodiments, R 2 is an unsubstituted tetrahydropyranyl group and R 3 For hydrogen.

[0019] In some embodiments, the compound of formula (I-59) is selected from compounds of formula (I-A59), (I-B59), or (I-C59):

[0020]

[0021] In some embodiments, the compound of formula (I-59) is selected from compounds of formula (I-B59):

[0022]

[0023] In some embodiments, the compound of formula (I-59) is selected from compounds of formula (I-C59):

[0024]

[0025] In some embodiments, R 2 and R 3 At least one of them is hydrogen, C1-C6 alkyl, carbocyclic group or heterocyclic group; 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) is selected from the compound of formula (I-D59):

[0026]

[0027] In some embodiments, the compound of formula (I-59) is selected from compounds of formula (I-E59):

[0028]

[0029] In some embodiments, the compound of formula (I-59) is selected from compounds of formula (ID-i59) or (ID-ii59):

[0030]

[0031] In some embodiments, the compound of formula (I-59) is selected from compounds of formula (IE-i59) or (IE-ii59):

[0032]

[0033] In some embodiments, the compound is:

[0034]

[0035]

[0036]

[0037] In one aspect, provided herein are compounds according to formula (I-66):

[0038]

[0039] or a pharmaceutically acceptable salt thereof, wherein: R 1 is an alkyl group (e.g., a C1-C6 alkyl group); 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 are each independently hydrogen, halogen 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 , together with the carbon atom to which they are attached, form an oxo group; R 6 is absent or is hydrogen; and represents a single bond or a double bond, where When one of them is a double bond, the other is a single bond; when two When both are single bonds, then R 6 is hydrogen; and when When one of them is a double bond, R 6 Does not exist.

[0040] In some embodiments, R 1 is an alkyl group (eg, a C1-C6 alkyl group). 1 is C1-C6 alkyl (e.g., -CH3, -CH2CH3, -CH2OCH3, or -CF3). 1 is -CH3, -CF3 or -CH2CH3. In some embodiments, R 1 -CH2OR A , where R A is a C1-C6 alkyl group (e.g., a C1-C3 alkyl group).

[0041] It is understood that the C1-C6 alkyl, aralkyl, heteroaralkyl, aryl, carbocyclyl, heterocyclyl, aryl, heteroaryl or heteroaryl group may be substituted or unsubstituted, for example, substituted with cyano, halogen, OH, or alkoxy.

[0042] 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).

[0043] In some embodiments, R 3 is hydrogen or alkyl (e.g., C1-C6 alkyl). 3 is hydrogen, unsubstituted alkyl (eg, unsubstituted C1-C6 alkyl), or halogenated alkyl (eg, -CF3).

[0044] In some embodiments, R 4 is –OH or halogen (e.g., -F).

[0045] 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 halogen (e.g., -F). In some embodiments, R 4 and R 5 is halogen (e.g., -F). In some embodiments, R 4 and R 5 For hydrogen.

[0046] In some embodiments, R 2is aryl (e.g., substituted or unsubstituted aryl, for example, substituted or unsubstituted phenyl), heteroaryl (e.g., substituted or unsubstituted heteroaryl, for example, substituted or unsubstituted pyridyl), aralkyl (e.g., substituted or unsubstituted aralkyl, for example, substituted or unsubstituted benzyl), or heteroaralkyl and R 3 is hydrogen or alkyl (eg, unsubstituted C1-C6 alkyl, eg, C1-C6 haloalkyl). 2 is aryl (e.g., substituted or unsubstituted aryl, for example, substituted or unsubstituted phenyl), heteroaryl (e.g., substituted or unsubstituted heteroaryl, for example, substituted or unsubstituted pyridyl), aralkyl (e.g., substituted or unsubstituted aralkyl, for example, substituted or unsubstituted benzyl), or heteroaralkyl and R 3 is hydrogen, –CH3 or –CF3.

[0047] In some embodiments, R 1 is an alkyl group (e.g., a C1-C6 alkyl group), R 2 is aryl (e.g., substituted or unsubstituted aryl, for example, substituted or unsubstituted phenyl), heteroaryl (e.g., substituted or unsubstituted heteroaryl, for example, substituted or unsubstituted pyridyl), aralkyl (e.g., substituted or unsubstituted aralkyl, for example, substituted or unsubstituted benzyl), or heteroaralkyl, and R 3 is hydrogen, -CH3 or -CF3. In some embodiments, R 1 is –CH3 or –CH2CH3, R 2 is unsubstituted phenyl, unsubstituted pyridyl, or unsubstituted benzyl, and R 3 is hydrogen, –CH3 or –CF3.

[0048] In some embodiments, the compound of formula (I-66) is selected from compounds of formula (I-A66), (I-B66), or (I-C66):

[0049]

[0050]

[0051] In some embodiments, the compound of formula (I-66) is selected from compounds of formula (I-A66):

[0052]

[0053] In some embodiments, the compound is:

[0054]

[0055]

[0056] In one aspect, provided herein are compounds according to formula (I-61):

[0057]

[0058] or a pharmaceutically acceptable salt thereof, wherein: R 1 is hydrogen or alkyl (e.g., C1-C6 alkyl); R 2 and R 3 Each is independently hydrogen, alkyl, aryl, heteroaryl, carbocyclic or heterocyclic or R 2 and R 3 , together with the carbon atoms to which they are attached, form a 3-8 membered ring; R 4 and R 5 are each independently hydrogen, halogen or -OR C , where R C is hydrogen or alkyl (e.g., C1-C6 alkyl), or R 4 and R 5 , together with the carbon atom to which they are attached, form an oxo group; R 6 is absent or is hydrogen; and represents a single bond or a double bond, where When one of them is a double bond, the other is a single bond; when two When both are single bonds, then R 6 is hydrogen; and when When one of them is a double bond, R 6 Does not exist; provided that the following compounds are not included:

[0059]

[0060] In some embodiments, R 1 is alkyl (e.g., C1-C6 alkyl) or hydrogen. 1 is C2-C6 alkyl (e.g., C3-C6 alkyl) or hydrogen. In some embodiments, R 1 is substituted or unsubstituted C2-C6 alkyl (e.g., substituted or unsubstituted C3-C6 alkyl) or hydrogen. 1 is methyl or ethyl (eg, substituted or unsubstituted methyl or substituted or unsubstituted ethyl). In some embodiments, R 1 is a substituted or unsubstituted methyl or a substituted or unsubstituted ethyl. 1 In some embodiments, R 1 -CH2OR A , where R A is a C1-C6 alkyl group (e.g., a C1-C3 alkyl group).

[0061] 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). 2 In some embodiments, R 2 is isopropyl (eg, substituted or unsubstituted isopropyl). In some embodiments, R 2 is substituted or unsubstituted isopropyl. 2 is a haloalkyl group (eg, a C1-C6 haloalkyl group).

[0062] In some embodiments, R 2 and R 3 Each is independently alkyl (e.g., C1-C6 alkyl) or hydrogen. 2 and R 3 Each 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 3-8 membered ring. In some embodiments, R 2 and R 3 Each is independently hydrogen or C1-C6 alkyl (e.g., C2-C6 alkyl). 2 and R 3 are each independently hydrogen or substituted or unsubstituted C1-C6 alkyl, (eg, substituted or unsubstituted C2-C6 alkyl). 2 and R 3 Each is independently hydrogen or C3-C6 alkyl (e.g., isopropyl). 2 and R 3 Each is independently hydrogen or a substituted or unsubstituted C3-C6 alkyl group (eg, a substituted or unsubstituted isopropyl group).

[0063] In some embodiments, R 4 is -OH or halogen (eg, -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 halogen (e.g., -F). In some embodiments, R 4 and R 5 is halogen (e.g., -F). In some embodiments, R4 and R 5 For hydrogen.

[0064] In some embodiments, R 2 and R 3 In some embodiments, R 2 is a C1-C6 alkyl group and R 3 is a C2-C6 alkyl group (e.g., a C3-C6 alkyl group). 2 is a substituted or unsubstituted C1-C6 alkyl group and R 3 is a substituted or unsubstituted C2-C6 alkyl group (eg, a substituted or unsubstituted C3-C6 alkyl group). 1 is ethyl (eg, substituted or unsubstituted ethyl) and R 2 and R 3 is methyl (eg, substituted or unsubstituted methyl). In some embodiments, R 1 is a substituted or unsubstituted ethyl group and R 2 and R 3 is a substituted or unsubstituted methyl group. 1 is ethyl, R 2 is isopropyl, and R 3 In some embodiments, R 1 is a substituted or unsubstituted ethyl group, R 2 is a substituted or unsubstituted isopropyl group, and R 3 In some embodiments, R 1 is ethyl, R 2 is isopropyl, and R 3 In some embodiments, R 1 is a substituted or unsubstituted ethyl group, R 2 is a substituted or unsubstituted isopropyl group, and R 3 is a substituted or unsubstituted methyl group.

[0065] In some embodiments, the compound of formula (I-61) is a compound of formula (I-A61), (I-B61), or (I-C61):

[0066]

[0067] In some embodiments, the compound of formula (I-61) is selected from compounds of formula (I-C61):

[0068]

[0069] In some embodiments, the compound of formula (I-61) is selected from compounds of formula (I-A61):

[0070]

[0071] In some embodiments, the compound of formula (I-61) is selected from compounds of formula (IC-i61) or (IC-ii61):

[0072]

[0073] In some embodiments, the compound is:

[0074] In one aspect, the present invention relates to compounds of formula (I-62):

[0075]

[0076] or a pharmaceutically acceptable salt thereof, wherein: R 1 is hydrogen or alkyl (e.g., C1-C6 alkyl); R 2 and R 3 Each is independently hydrogen, alkyl, carbocyclic or heterocyclic or R 2 and R 3 , together with the carbon atoms to which they are attached, form a 3-8 membered ring; R 4 and R 5 are each independently hydrogen, halogen or -OR C , where R C is hydrogen or alkyl (e.g., C1-C6 alkyl), or R 4 and R 5 , together with the carbon atom to which they are attached, form an oxo group; R 6 is absent or is hydrogen; and represents a single bond or a double bond, where When one of them is a double bond, the other is a single bond; when two When both are single bonds, then R 6 is hydrogen; and when When one of them is a double bond, R 6 Does not exist.

[0077] In some embodiments, R 1 is an alkyl group (eg, a C1-C6 alkyl group). 1 is a substituted or unsubstituted C2-C6 alkyl group (eg, a substituted or unsubstituted C3-C6 alkyl group). 1 is methyl or ethyl (eg, substituted or unsubstituted methyl or substituted or unsubstituted ethyl). In some embodiments, R 1 is a substituted or unsubstituted methyl or a substituted or unsubstituted ethyl.1 In some embodiments, R 1 -CH2OR A , where R A is a C1-C6 alkyl group (e.g., a C1-C3 alkyl group).

[0078] 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). 2 is a haloalkyl group (eg, a C1-C6 haloalkyl group).

[0079] In some embodiments, R 2 and R 3 Each is independently hydrogen or C1-C6 alkyl (e.g., C2-C6 alkyl). 2 and R 3 are each independently hydrogen or substituted or unsubstituted C1-C6 alkyl (eg, substituted or unsubstituted C2-C6 alkyl). 2 and R 3 Each is independently alkyl (e.g., C1-C6 alkyl) or hydrogen. 2 and R 3 Each 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 3-8 membered ring.

[0080] In some embodiments, R 4 is -OH or halogen (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 halogen (e.g., -F). In some embodiments, R 4 and R 5 is halogen (e.g., -F). In some embodiments, R 4 and R 5 For hydrogen.

[0081] In some embodiments, R 1 is ethyl (eg, substituted or unsubstituted ethyl) and R 2 and R 3is methyl (eg, substituted or unsubstituted methyl). In some embodiments, R 1 is a substituted or unsubstituted ethyl group and R 2 and R 3 is a substituted or unsubstituted methyl group.

[0082] In some embodiments, the compound of formula (I-62) is a compound of formula (I-A62), (I-B62), or (I-C62):

[0083]

[0084] In some embodiments, the compound of formula (I-62) is selected from compounds of formula (I-C62):

[0085]

[0086] In some embodiments, the compound of formula (I-62) is selected from compounds of formula (I-A62):

[0087]

[0088] In some embodiments, R 1 is ethyl (eg, substituted or unsubstituted ethyl) and R 2 and R 3 is methyl (eg, substituted or unsubstituted methyl). In some embodiments, R 1 is a substituted or unsubstituted ethyl group and R 2 and R 3 is a substituted or unsubstituted methyl group.

[0089] In some embodiments, the compound of formula (I-62) is selected from compounds of formula (IC-i62) or (IC-ii62):

[0090]

[0091] In some embodiments, the compound is

[0092]

[0093] In one aspect, provided herein are compounds according to formula (I-60):

[0094]

[0095] or a pharmaceutically acceptable salt thereof, wherein: R 2 and R 3 are each independently hydrogen, alkyl (e.g., C1-C6 alkyl), carbocyclyl, heterocyclyl, aryl or heteroaryl, or R 2 and R3 , together with the carbon atoms to which they are attached, form a 3-8 membered ring; R 4 and R 5 are each independently hydrogen, halogen or -OR C , where R C is hydrogen or alkyl (e.g., C1-C6 alkyl), or R 4 and R 5 , together with the carbon atom to which they are attached, form an oxo group; R 6 is absent or is hydrogen; and represents a single bond or a double bond, where When one of them is a double bond, the other is a single bond; when two When both are single bonds, then R 6 is hydrogen; and when When one of them is a double bond, R 6 Does not exist.

[0096] In some embodiments, R 2 is alkyl (e.g., C1-C6 alkyl) or hydrogen. 2 is a haloalkyl group (eg, a C1-C6 haloalkyl group). 2 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl) or hydrogen. 2 is an aryl group or a heteroaryl group.

[0097] In some embodiments, R 2 and R 3 Each is independently alkyl (e.g., C1-C6 alkyl) or hydrogen. 2 and R 3 Each is independently substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl) or hydrogen. 2 and R 3 Each is independently unsubstituted alkyl (e.g., unsubstituted C1-C6 alkyl) or hydrogen. 2 and R 3 Each is independently C1-C6 haloalkyl (e.g., trifluoromethyl) or hydrogen. In some embodiments, R 2 and R 3 Each is independently aryl or heteroaryl. In some embodiments, R 2 and R 3 , together with the carbon atom to which they are attached, form a 3-membered ring.

[0098] 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 3-8 membered carbocyclic or heterocyclic ring.

[0099] In some embodiments, R 2 is a carbocyclic or heterocyclic group and R 3 In some embodiments, R 2 is trifluoromethyl and R 3 In some embodiments, R 2 is an aryl or heteroaryl group and R 3 In some embodiments, R 2 and R 3 is methyl (eg, substituted or unsubstituted methyl). In some embodiments, R 2 and R 3 In some embodiments, R 2 and R 3 is an unsubstituted methyl group.

[0100] In some embodiments, R 4 is -OH or halogen (eg, -F). In some embodiments, R 4 and R 5 , together with the carbon atom to which they are attached, form an oxo group.

[0101] In some embodiments, R 4 is hydrogen and R 5 is halogen (e.g., -F). In some embodiments, R 4 and R 5 is halogen (e.g., -F). In some embodiments, R 4 and R 5 For hydrogen.

[0102] In some embodiments, the compound of formula (I-60) is selected from compounds of formula (I-A60), (I-B60), or (I-C60):

[0103]

[0104] In some embodiments, the compound of formula (I-60) is selected from compounds of formula (I-B60):

[0105]

[0106] In some embodiments, R 2 and R 3 At least one of them is C1-C6 alkyl, carbocyclic group, heterocyclic group, aryl or heteroaryl; or R2 and R 3 , together with the carbon atoms to which they are attached, form a 3-8 membered ring.

[0107] In some embodiments, R 2 is methyl and R 3 In some embodiments, R 2 is an unsubstituted methyl group and R 3 In some embodiments, R 2 and R 3 For hydrogen.

[0108] In some embodiments, the compound is:

[0109]

[0110] 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.

[0111] In one aspect, provided herein are methods of inducing sedation or anesthesia, comprising administering to a subject an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0112] In one aspect, provided herein are methods for treating or preventing a disease described herein, 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.

[0113] In some embodiments, the disease is a metabolic disease.

[0114] In some embodiments, the disease is an autoimmune disease.

[0115] In some embodiments, the disease is rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and plaque psoriasis.

[0116] In some embodiments, the disease is a gastrointestinal (GI) disorder, e.g., constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) (e.g., ulcerative colitis, Crohn's disease), a structural disorder affecting the gastrointestinal tract, anal disorders (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas), colon polyps, cancer, or colitis.

[0117] In some embodiments, the disease is inflammatory bowel disease.

[0118] In some embodiments, the disease is cancer, diabetes, or a sterol synthesis disorder.

[0119] In some embodiments, the disease 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 syndrome, schizophrenia, and traumatic brain injury.

[0120] In one aspect, provided herein are methods for treating or preventing CNS-related disorders, 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. In some embodiments, the CNS-related disorder is adjustment disorder, anxiety disorder (including obsessive-compulsive disorder, post-traumatic stress disorder, and social phobia), cognitive disorder (including Alzheimer's disease and other forms of dementia (e.g., frontotemporal dementia), dissociative disorder, eating disorder, mood disorder (including depression (e.g., postpartum depression), bipolar disorder, dysthymic disorder, suicidality), schizophrenia or other psychotic disorder (including schizoaffective disorder), sleep disorder (including insomnia), substance-related disorder, personality disorder (including obsessive-compulsive personality disorder), autism spectrum disorder, The invention also includes, but is not limited to, leukemia, myeloma, encephalopathy, encephalopathy (including those associated with mutations in Shank family proteins, including Shank3), neurodevelopmental disorders (including Rett syndrome, tuberous sclerosis complex), multiple sclerosis, sterol synthesis disorders, pain (including acute and chronic pain; headaches, e.g., migraines), encephalopathy secondary to a medical condition (including hepatic encephalopathy and anti-NMDA receptor encephalitis), epilepsy (including status epilepticus and monogenic forms of epilepsy, such as Dravet disease), stroke, traumatic brain injury, movement disorders (including Huntington's disease and Parkinson's disease), vision impairment, hearing loss, or tinnitus.

[0121] In some embodiments, the disease is Huntington's disease. In some embodiments, the disease is Parkinson's disease. In some embodiments, the disease is an inflammatory disease (e.g., lupus).

[0122] In some embodiments, the disease is a sterol synthesis disorder.

[0123] In some embodiments, the disease is Smith-Lemli-Opitz syndrome (SLOS). In some embodiments, the disease is streptosterolosis. In some embodiments, the disease is sitosterolemia. In some embodiments, the disease is cerebrotendinous xanthomatosis (CTX). In some embodiments, the disease is mevalonate kinase deficiency (MKD). In some embodiments, the disease is SC4MOL gene mutation (SMO Deficiency). In some embodiments, the disease is Niemann-Pick disease. In some embodiments, the disease is autism spectrum disorder (ASD). In some embodiments, the disease is associated with phenylketonuria.

[0124] Other objects and advantages will become apparent to those skilled in the art from consideration of the ensuing detailed description, examples, and claims.

[0125] definition

[0126] Chemical definition

[0127] The following describes in more detail the definitions of specific functional groups and chemical terms. Chemical elements are defined according to the CAS version of the Periodic Table of the Elements in the Handbook of Chemistry and Physics, 75th edition, inside pages, and specific functional groups are generally defined as described therein. In addition, 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, 3 rd General principles of organic chemistry as well as specific functional groups and reactivities are described in Organic Chemistry: ...

[0128] The compounds described herein may contain one or more asymmetric centers and, therefore, may exist in different 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 separated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, p. 268 (ELE Liel, Ed., Univ. of Notre Dame press, Notre Dame, IN 1972). The present invention also includes the compounds described herein as individual isomers, substantially free of other isomers, or as mixtures of different isomers.

[0129] As used herein, "enantiomeric excess" ("ee") or "% enantiomeric excess" ("%ee") of a composition 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, e.g., the R enantiomer.

[0130] ee=(90-10) / 100=80%.

[0131] Thus, a composition containing 90% of one enantiomer and 10% of the other enantiomer is said to have an enantiomeric excess of 80%.

[0132] As used herein, "diastereomeric excess" ("de") or "diastereomeric excess" ("% de") of a composition 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.

[0133] de = (90 - 10) / 100 = 80%.

[0134] 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%.

[0135] In an alternative embodiment, 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 may be, for example, 13 C or 14 C; oxygen may be, for example, 18 O; nitrogen may 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 in the compound.

[0136] When a numerical range is listed, it is intended to include all values ​​and sub-ranges within that range. For example, "C 1-6 "Alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-5 、C 2-4 、C 2-3 、C 3-6 、C 3-5 、C 3-4 、C 4-6 、C 4-5 and C 5-6 alkyl.

[0137] The following terms are intended to have the following meanings as shown, and to assist in understanding the description of the present invention and the desired scope. When describing the present invention (which may include compounds, pharmaceutical compositions comprising the compounds, and methods of using the compounds and compositions), unless otherwise stated, the following terms (if present) have the following meanings. It should also be understood that when described herein, any portion defined below may be substituted by a variety of substituents, and each definition is intended to include these substituted portions within the scope defined below. Unless otherwise stated, the term "substituted" is defined as follows. It should be further understood that the terms "group" and "atomic radical" can be considered interchangeable when used herein. The articles "a" and "an" can be used herein to refer to one grammatical object or more than one (i.e., at least one) grammatical object of the article. For example, "an analog" refers to one or more than one analog.

[0138] "Aliphatic" means an alkyl, alkenyl, alkynyl or carbocyclyl group as defined herein.

[0139] "Carbocyclylalkyl" refers to an alkyl group in which the alkyl group is substituted by a cycloalkyl group. Common carbocyclylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl.

[0140] "Heterocyclylalkyl" refers to an alkyl group in which the alkyl group is substituted with a heterocyclyl group. Common heterocyclylalkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, and the like.

[0141] "Aralkyl" is a subset of alkyl and aryl as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group.

[0142] "Alkyl" refers to a straight or branched chain 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 1-7In some embodiments, an alkyl group has 1 to 6 carbon atoms ("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 1-2 In some embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C 2-6 C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). Other examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, an alkyl group is independently optionally substituted at each occurrence, i.e., unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents (e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent). In some embodiments, the alkyl group is an unsubstituted C 1-10 In some embodiments, the alkyl group is a substituted C 1-10 Alkyl. Commonly used alkyl abbreviations include Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2).

[0143] "Alkylene" refers to an alkyl group in which two hydrogens are removed to provide a divalent group, and may be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted alkylene groups, such as those substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-), and the like. When carbon ranges or values ​​are given for a particular alkylene group, it is understood that the ranges or values ​​refer to carbon ranges or values ​​in a linear carbon divalent chain. Alkylene groups may be substituted with one or more substituents described herein or may be unsubstituted.

[0144] "Alkenyl" refers to a straight or branched chain hydrocarbon radical ("C") 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). 2-20 In some embodiments, the alkenyl group does not contain any triple bonds. In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C 2-10 In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2-5 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 2-3In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (as in 2-butenyl) or terminal (as in 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 the alkenyl group include the aforementioned C 2-4 Examples of alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Other examples of alkenyl groups include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each 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 some embodiments, the alkenyl group is an unsubstituted C 2-10 In some embodiments, the alkenyl group is a substituted C 2-10 Alkenyl.

[0145] "Alkynyl" refers to a straight or branched chain hydrocarbon radical ("C") 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). 2-20 In some embodiments, the alkynyl group does not contain any double bonds. In some embodiments, the alkynyl group has 2 to 10 carbon atoms ("C 2-10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, an alkynyl group has 2 carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (as in 2-butynyl) or terminal (as in 1-butynyl). C 2-4Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2-6 Examples of the alkynyl group include the aforementioned C 2-4 Alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Other examples of alkynyl groups include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each alkynyl group is independently optionally substituted, i.e., unsubstituted (“unsubstituted alkynyl”) or substituted with one or more substituents (e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent) (“substituted alkynyl”). In some embodiments, the alkynyl group is an unsubstituted C 2-10 In some embodiments, the alkynyl group is a substituted C 2-10 Alkynyl.

[0146] As used herein, the term "heteroalkyl" 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 the parent chain, wherein the one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain, and / or one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In some embodiments, a heteroalkyl group refers to a saturated group ("heteroalkyl") having 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms. 1-10 In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC 1-9 In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC 1-8 In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC 1-7 In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroC 1-6 In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroC 1-5 In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms (“heteroC 1-4 In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroC 1-3 In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“heteroC 1-2In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroC1 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms ("heteroC1 2-6 Unless otherwise specified, each heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In some embodiments, the heteroalkyl group is an unsubstituted heteroC 1-10 In some embodiments, the heteroalkyl group is a substituted heteroC 1-10 alkyl.

[0147] "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a ring arrangement) having 6-14 ring carbon atoms and 0 heteroatoms in the aromatic ring system ("C 6-14 In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10 In some embodiments, an aryl group has fourteen ring carbon atoms ("C 14 "Aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, wherein the radical or point of attachment is on the aryl ring, and in such case the number of carbon atoms is continued to be specified as 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, pentadiene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubrocene, triphenylene, and trinaphthalene. Specific aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted ("substituted aryl") with one or more substituents. In some embodiments, an aryl group is an unsubstituted C 6-14 In some embodiments, the aryl group is a substituted C 6-14 Aryl.

[0148] In some embodiments, the aryl group is substituted with one or more groups selected from halogen, C1-C8 alkyl, C1-C8 haloalkyl, cyano, hydroxy, C1-C8 alkoxy, and amino.

[0149] Representative examples of substituted aryl groups include the following:

[0150]

[0151] where R 56 and R 57 One of them can be hydrogen and R 56 and R 57 At least one of them is independently selected from C1-C8 alkyl, C1-C8 haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 NR 58 SOR 59 NR 58 SO2R 59 、COO alkyl、COO aryl、CONR 58 R 59 、CONR 58 OR59 NR 58 R 59 、SO2NR 58 R 59 , S-alkyl, SO alkyl, SO 2 alkyl, S aryl, SO aryl, SO 2 aryl; or R 56 and R 57 may combine to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms, optionally containing one or more heteroatoms selected from N, O or S. R 60 and R 61 are independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 Aryl, substituted C6-C 10 aryl, 5- to 10-membered heteroaryl, or substituted 5- to 10-membered heteroaryl.

[0152] "Fused aryl" refers to an aryl group having two of its ring carbon atoms shared with a second aryl or heteroaryl ring or with a carbocyclyl or heterocyclyl ring.

[0153] "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 ring arrangement) having ring carbon atoms and 1 to 4 ring heteroatoms in the aromatic ring system, wherein 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, as valence permits. Heteroaryl bicyclic ring systems may contain one or more heteroatoms within one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, wherein the point of attachment is on the heteroaryl ring, and in such cases, the number of ring members continues to be specified as 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 is on either the aryl or heteroaryl ring, and in this case, the number of ring members is specified as the number of ring members in the fused (aryl / heteroaryl) ring system. For bicyclic heteroaryl groups in which one ring does not contain heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on the ring with the heteroatom (e.g., 2-indolyl) or on the ring without the heteroatom (e.g., 5-indolyl).

[0154] In some embodiments, a heteroaryl group is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 10-membered heteroaryl”). In some embodiments, a heteroaryl group is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heteroaryl”). In some embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heteroaryl”). In some embodiments, the 5- to 6-membered heteroaryl group has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl group has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl group has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each heteroaryl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl") with one or more substituents. In some embodiments, the heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl group. In some embodiments, the heteroaryl group is a substituted 5- to 14-membered heteroaryl group.

[0155] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepine, oxepinyl, and thiepine. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0156] Examples of representative heteroaryl groups include the following:

[0157]

[0158] wherein each Z is selected from carbonyl, N, NR 65 , O and S; and R 65 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl and 5- to 10-membered heteroaryl.

[0159] "Carbocyclyl" or "carbocycle" refers to a non-aromatic ring system having 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, the carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3-7 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 (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C 3-8 Carbocyclyl groups include but are not limited to the aforementioned C 3-6 Carbocyclyl groups and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo [2.2.1] heptyl (C7), bicyclo [2.2.2] octyl (C8), etc. Exemplary C 3-10 Carbocyclyl groups include but are not limited to the aforementioned C 3-8 Carbocyclyl groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10) and the like. As described in the previous examples, in some embodiments, the carbocyclyl group is a monocyclic ring ("monocyclic carbocyclyl") or comprises a fused, bridged or spirocyclic ring system (such as a bicyclic ring system ("bicyclic carbocyclyl")), and may be saturated or may be partially unsaturated. "Carbocyclyl" also includes ring systems in which the carbocyclyl ring as described above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the carbocyclyl ring, and in this case, the number of carbons continues to be designated as the number of carbons in the carbocyclyl ring system. Unless otherwise stated, each carbocyclyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted ("substituted carbocyclyl") by one or more substituents. In some embodiments, the carbocyclyl group is an unsubstituted C 3-10 In some embodiments, the carbocyclyl group is a substituted C 3-10 Carbocyclic group.

[0160] In some embodiments, "carbocyclyl" is a monocyclic saturated carbocyclyl group ("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 5-6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5-10 Cycloalkyl”). C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C6). 3-6 Examples of the cycloalkyl group include the aforementioned C 5-6 Cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). 3-8 Examples of the cycloalkyl group include the aforementioned C 3-6 Cycloalkyl groups and cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") with one or more substituents. In some embodiments, the cycloalkyl group is unsubstituted C 3-10 In some embodiments, the cycloalkyl group is substituted C 3-10 Cycloalkyl.

[0161] "Heterocyclyl" or "heterocycle" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein 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 may be a carbon or nitrogen atom, as valence permits. A heterocyclyl group may be a monocyclic ring ("monocyclic heterocyclyl") or a fused, bridged, or spiro ring system, such as a bicyclic ring system ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may 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 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, and in such cases, the number of ring members continues to be specified as the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted ("substituted heterocyclyl") with one or more substituents. In some embodiments, a heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In some embodiments, a heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0162] In some embodiments, the heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclyl”). In some embodiments, the heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, the heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0163] Exemplary 3-membered heterocyclic groups containing one heteroatom include but are not limited to aziridine, oxirane, and thiirane. Exemplary 4-membered heterocyclic groups containing one heteroatom include but are not limited to azetidinyl, oxetane, and thiirane. Exemplary 5-membered heterocyclic groups containing one heteroatom include but are not limited to tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrole-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include but are not limited to dioxolane, oxathiolanyl (oxasulfuranyl), dithiolanyl (disulfuranyl) and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include but are not limited to triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thiohexyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithiohexyl, and dioxane. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepane, and thioheptanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxocanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocycles) include, but are not limited to, dihydroindole, isoindole, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocycle) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0164] "Nitrogen-containing heterocyclic group" refers to a 4- to 7-membered non-aromatic cyclic group containing at least one nitrogen atom, such as, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine and N-alkylpiperazines such as N-methylpiperazine. Specific examples include azetidine, piperidone and piperazinone.

[0165] When used to describe a compound or a group present on a compound, "hetero" means that one or more carbon atoms in the compound or group are replaced by nitrogen, oxygen, or sulfur heteroatoms. Hetero can be used to describe any of the above-mentioned hydrocarbon groups, such as alkyl (e.g., heteroalkyl), cycloalkyl (e.g., heterocyclyl), aryl (e.g., heteroaryl), cycloalkenyl (e.g., cycloheteroalkenyl), etc., which have 1 to 5, especially 1 to 3 heteroatoms.

[0166] "Acyl" refers to -C(O)R 20 Group, where R 20 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein. "Alkanoyl" is an acyl group in which R 20 is a group other than hydrogen. Representative acyl groups include, but are not limited to, formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), --C(O)-C1-C8 alkyl, -C(O)-(CH2) t (C6-C 10 Aryl), -C(O)-(CH2) t (5- to 10-membered heteroaryl), -C(O)-(CH2) t (C3-C 10 Cycloalkyl) and -C(O)-(CH2) t (4- to 10-membered heterocyclyl), wherein t is an integer from 0 to 4. In some embodiments, R 21 is a C1-C8 alkyl group substituted by halogen or hydroxy; or a C3-C 10 Cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 aryl, arylalkyl, 5- to 10-membered heteroaryl, or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy, or hydroxy.

[0167] "Alkoxy" refers to the group -OR 29 , where R 29is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. Specific alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Specific alkoxy groups are lower alkoxy groups, i.e., groups having 1 to 6 carbon atoms. Further specific alkoxy groups have 1 to 4 carbon atoms.

[0168] In some embodiments, R 29 is a group having one or more substituents, for example 1 to 5 substituents, and specifically 1 to 3 substituents, especially 1 substituent, which is selected from amino, substituted amino, C6-C 10 Aryl, aryloxy, carboxyl, cyano, C3-C 10 Cycloalkyl, 4 to 10 membered heterocyclyl, halogen, 5 to 10 membered heteroaryl, hydroxy, nitro, thioalkoxy, thioaryloxy, mercapto, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2- and aryl-S(O)2-. Exemplary 'substituted alkoxy' include, but are not limited to, -O-(CH2) t (C6-C 10 Aryl), -O-(CH2) t (5- to 10-membered heteroaryl), -O-(CH2) t (C3-C 10 Cycloalkyl) and -O-(CH2) t (4- to 10-membered heterocyclyl), wherein t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl or heterocyclyl group present may itself be substituted with unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy. Specific exemplary 'substituted alkoxy' groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH and -OCH2CH2NMe2.

[0169] "Amino" refers to the group -NH2.

[0170] "Oxo" refers to -C(=O)-.

[0171] "Substituted amino" refers to a group of the formula -N(R 38 )2 amino group, wherein R 38is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group or amino protecting group, wherein at least one R 38 is not hydrogen. In some embodiments, each R 38 independently selected from hydrogen, C1-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclic group or C3-C 10 Cycloalkyl; or C1-C8 alkyl, which is substituted by halogen or hydroxy; C3-C8 alkenyl, which is substituted by halogen or hydroxy; C3-C8 alkynyl, which is substituted by halogen or hydroxy; or -(CH2) t (C6-C 10 Aryl), -(CH2) t (5- to 10-membered heteroaryl), -(CH2) t (C3-C 10 Cycloalkyl) or -(CH2) t (4- to 10-membered heterocyclyl), wherein t is an integer from 0 to 8, each of which is substituted with unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; or two R 38 The groups combine to form an alkylene group.

[0172] Exemplary "substituted amino" include, but are not limited to, -NR 39 -C1-C8 alkyl, -NR 39 -(CH2) t (C6-C 10 Aryl), -NR 39 -(CH2) t (5- to 10-membered heteroaryl), -NR 39 -(CH2) t (C3-C 10 Cycloalkyl) and -NR 39 -(CH2) t (4- to 10-membered heterocyclic group), wherein t is an integer from 0 to 4, such as 1 or 2, and each R 39and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group may be substituted with unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy, or 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 groups include monosubstituted and disubstituted amino groups.

[0173] "Carboxyl" refers to a -C(O)OH group.

[0174] "Cyano" refers to a -CN group.

[0175] "Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In some embodiments, the halo group is fluoro or chloro.

[0176] "Haloalkyl" refers to an alkyl group in which the alkyl group is substituted with one or more halogens. Typical haloalkyl groups include, but are not limited to, trifluoromethyl (-CF3), difluoromethyl (-CHF2), fluoromethyl (-CH2F), chloromethyl (-CH2Cl), dichloromethyl (-CHCl2), tribromomethyl (-CH2Br), etc.

[0177] "Hydroxy" refers to the radical -OH.

[0178] "Nitro" refers to the radical -NO2.

[0179] "Thioketo" refers to the group =S.

[0180] 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 or not preceded by the term "optionally," means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, such as a substituent whose substitution results in a stable compound (e.g., a compound that does not spontaneously transform, such as 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 substituent at each position may be the same or different. The term "substituted" is considered to include substitution with all permissible substituents of organic compounds, any of which results in the formation of stable compounds as described herein. The present invention contemplates any and all such combinations to obtain stable compounds. For purposes herein, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents as described herein which satisfy the valences of the heteroatoms and result in the formation of a stable moiety.

[0181] Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa 、-ON(R bb )2、-N(R bb )2、-N(R bb )3 + X - 、-N(OR cc )R bb 、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2, -CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb)2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NRbb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(R cc )3、-B(R aa )2、-B(OR cc )2, -BR aa (OR cc ), C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3 to 14 membered heterocyclic group, C 6-14 Aryl and 5- to 14-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0182] Or the two geminal hydrogens on the carbon atom are replaced by groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa 、=NNR bb C(=O)OR aa 、=NNR bb S(=O)2R aa 、=NR bb or = NOR cc replace;

[0183] R aa Each occurrence is independently selected from C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3 to 14 membered heterocyclic group, C 6-14 Aryl and 5- to 14-membered heteroaryl, or two R aa to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group is independently replaced by 0, 1, 2, 3, 4, or 5 R dd group substitution;

[0184] R bb Each occurrence is independently selected from hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc )2, -CO2Raa 、-SO2R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc )2, -SO2R cc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa 、-P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc )2、C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3 to 14 membered heterocyclic group, C 6-14 Aryl and 5- to 14-membered heteroaryl, or two R bb The groups are combined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group is independently replaced by 0, 1, 2, 3, 4, or 5 R dd group substitution;

[0185] R cc Each occurrence is independently selected from hydrogen, C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3 to 14 membered heterocyclic group, C 6-14 Aryl and 5- to 14-membered heteroaryl, or two R cc The groups are combined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group is independently replaced by 0, 1, 2, 3, 4, or 5 R dd group substitution;

[0186] R dd Each occurrence is independently selected from 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 , -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, C1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, 3 to 10 membered heterocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R gg Group substitution, or two geminal R dd Substituents may combine to form =O or =S;

[0187] R ee Each occurrence is independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, 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 replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0188] R ff Each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, 3 to 10 membered heterocyclic group, C 6-10 Aryl and 5- to 10-membered heteroaryl, or two R ff The groups are combined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group is independently replaced by 0, 1, 2, 3, 4, or 5 R gg group substitution; and

[0189] R gg Each occurrence is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - 、-NH(C 1-6 Alkyl)2 + X - 、-NH2(C 1-6 alkyl) + X- 、-NH3 + X - 、-N(OC 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 Alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3-C(=S)N(C 1-6alkyl)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 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, C 6-10 aryl, 3- to 10-membered heterocyclic group, 5- to 10-membered heteroaryl; or two geminal R gg Substituents may combine to form =O or =S; where X - For the counter ion.

[0190] "Counter ions" or "anionic counterions" are negatively charged groups that associate with cationic quaternary amino groups to maintain electrical neutrality. Exemplary counterions include halides (e.g., - 、Cl - Br - , I - )、NO3 - 、ClO4 - OH - 、H2PO4 - 、HSO4 - 、SO4 -2 , sulfonate ions (such as 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 (such as acetate, acetate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0191] Nitrogen atoms may be substituted or unsubstituted as valence permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc )2, -CO2R aa 、-SO2R aa 、-C(=NRbb )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 Halogenated alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3 to 14 membered heterocyclic group, C 6-14 Aryl and 5- to 14-membered heteroaryl, or two R cc The groups are combined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group is independently replaced by 0, 1, 2, 3, 4, or 5 R dd Group substitution, where R aa 、R bb 、R cc and R dd As mentioned above.

[0192] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims.It is not intended that the present invention be limited in any way to the exemplary substituents listed above.

[0193] Other definitions

[0194] The term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without producing toxicity, irritation, allergic reactions, etc., within the scope of health medical judgment, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are 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 those derived from suitable inorganic and organic acids and inorganic and organic bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts formed of an amino group with an inorganic acid (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with an organic acid (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or salts formed by using other methods in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1-4 Representative alkali metal or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, and the like. Pharmaceutically acceptable salts also include non-toxic ammonium salts, quaternary ammonium salts, and amine cation salts formed using counterions (such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates), as appropriate.

[0195] "Subjects" to be administered include, but are not limited to, humans (i.e., males or females of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly people)) and / or non-human animals, such as mammals (e.g., primates (e.g., macaques, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs). In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0196] Disease, disorder, and condition are used interchangeably herein.

[0197] As used herein, and unless otherwise indicated, the terms "treat," "treating," and "treatment" refer to measures taken while a subject has a particular disease, disorder, or condition that reduces the severity of, or slows or prevents the progression of, the disease, disorder, or condition ("therapeutic treatment"), and also refer to actions taken before a subject develops a particular disease, disorder, or condition ("prophylactic treatment").

[0198] Generally, an "effective amount" of a compound is an amount sufficient to elicit a desired biological response. Those skilled in the art will appreciate that the effective amount of a compound of the invention may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject. An effective amount encompasses both therapeutic and prophylactic treatments.

[0199] As used herein and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic effect in the treatment of a disease, disorder, or condition, or sufficient to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent that provides a therapeutic effect in the treatment of a disease, disorder, or condition when used alone or in combination with other therapies. The term "therapeutically effective amount" can include an amount that generally improves treatment, reduces or avoids symptoms or causes of a disease or condition, or increases the efficacy of another therapeutic agent.

[0200] As used herein and 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 a disease, disorder, or condition, or to avoid its recurrence. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent that provides a prophylactic effect in the prevention of a disease, disorder, or condition when used alone or in combination with other agents. The term "prophylactically effective amount" can include an amount that generally improves prevention or increases the prophylactic effect of another prophylactic agent.

[0201] Detailed description of some embodiments of the invention

[0202] As generally described herein, the present invention provides substituted oxysterols for use in preventing and / or treating a variety of diseases, including but not limited to NMDA-mediated diseases.

[0203] Compound

[0204] In one aspect, provided herein are compounds according to formula (I-59):

[0205]

[0206] or a pharmaceutically acceptable salt thereof, wherein: R 2 and R 3 are each independently hydrogen, alkyl (e.g., C1-C6 alkyl), carbocyclic or heterocyclic, or R 2 and R 3 , together with the carbon atoms to which they are attached, form a 3-8 membered ring; R 4 and R 5 are each independently hydrogen, halogen or -OR C , where R C is hydrogen or alkyl (e.g., C1-C6 alkyl), or R 4 and R 5 , together with the carbon atom to which they are attached, form an oxo group; R 6 is absent or is hydrogen; and represents a single bond or a double bond, where When one of them is a double bond, the other is a single bond; when two When both are single bonds, then R 6 is hydrogen; and when When one of them is a double bond, R 6 Does not exist; provided that the following compounds are not included:

[0207]

[0208] In some embodiments, R 2 is hydrogen or alkyl (e.g., C1-C6 alkyl). 2 is a haloalkyl group (eg, a C1-C6 haloalkyl group).

[0209] In some embodiments, R 2 and R 3 Each is independently alkyl (e.g., substituted C1-C6 alkyl) or hydrogen. 2 and R 3 Each is independently unsubstituted alkyl (e.g., unsubstituted C1-C6 alkyl) or hydrogen. 2 and R3 Each is independently C1-C6 haloalkyl (e.g., trifluoromethyl) or hydrogen. In some embodiments, R 2 and R 3 Each is independently hydrogen, carbocyclyl or heterocyclyl. In some embodiments, R 2 and R 3 Each is independently C2-C6 alkyl (e.g., isopropyl or tert-butyl) or hydrogen. 2 and R 3 Each is independently hydrogen or C3-C6 alkyl (eg, isopropyl or tert-butyl).

[0210] In some embodiments, R 2 and R 3 At least one of them is C3-C6 alkyl (e.g., isopropyl or tert-butyl), carbocyclic or heterocyclic; 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, R 2 is isopropyl or tert-butyl and R 3 is methyl or hydrogen. In some embodiments, R 2 is 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 In some embodiments, R 2 is a substituted tert-butyl group and R 3 In some embodiments, R 2 is an unsubstituted tert-butyl group and R 3 In some embodiments, R 2 is trifluoromethyl and R 3 In some embodiments, R 2 is trifluoromethyl and R 3 In some embodiments, R 2 is trifluoromethyl and R 3 In some embodiments, R 2 is trifluoromethyl and R 3 In some embodiments, R 2 is methyl and R 3 In some embodiments, R 2 is a substituted methyl group and R 3 In some embodiments, R 2is an unsubstituted methyl group and R 3 For hydrogen.

[0211] In some embodiments, R 4 is -OH or halogen (eg, -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 halogen (e.g., -F). In some embodiments, R 4 and R 5 is halogen (e.g., -F). In some embodiments, R 4 and R 5 For hydrogen.

[0212] In some embodiments, R 2 and R 3 , together with the carbon atoms to which they are attached, form a 5-membered ring. In some embodiments, R 2 is a C2-C6 alkyl group (eg, a substituted or unsubstituted isopropyl group or a substituted or unsubstituted tert-butyl group) and R 3 is C1-C6 alkyl (eg, substituted or unsubstituted C1-C6 alkyl). In some embodiments, R 2 is an unsubstituted C2-C6 alkyl group (eg, an unsubstituted isopropyl group or an unsubstituted tert-butyl group) and R 3 is an unsubstituted C1-C6 alkyl. 2 and R 3 , together with the carbon atom to which they are attached, form a 6-membered ring.

[0213] In some embodiments, R 2 is a carbocyclic or heterocyclic group and R 3 In some embodiments, R 2 and R 3 In some embodiments, R 2 isopropyl and R 3 In some embodiments, R 2 is substituted isopropyl and R 3 In some embodiments, R 2 is substituted isopropyl and R 3 In some embodiments, R 2 and R 3, together with the carbon atoms to which they are attached, form a 3-8 membered carbocyclic (e.g., cyclohexyl) or heterocyclic (e.g., tetrahydrofuranyl or tetrahydropyranyl) ring. In some embodiments, the carbocyclic or heterocyclic ring is substituted (e.g., a ring substituted with 1 or 2 halogen or alkyl groups). In some embodiments, R 2 is cyclobutyl and R 3 In some embodiments, R 2 is tetrahydropyranyl and R 3 For hydrogen.

[0214] In some embodiments, R 2 is a substituted cyclobutyl group and R 3 In some embodiments, R 2 is a substituted tetrahydropyranyl group and R 3 In some embodiments, R 2 is an unsubstituted cyclobutyl group and R 3 In some embodiments, R 2 is an unsubstituted tetrahydropyranyl group and R 3 For hydrogen.

[0215] In some embodiments, the compound of formula (I-59) is selected from compounds of formula (I-A59), (I-B59), or (I-C59):

[0216]

[0217]

[0218] In some embodiments, the compound of formula (I-59) is selected from compounds of formula (I-B59):

[0219]

[0220] In some embodiments, the compound of formula (I-59) is selected from compounds of formula (I-C59):

[0221]

[0222] In some embodiments, R 2 and R 3 At least one of them is hydrogen, C1-C6 alkyl, carbocyclic group or heterocyclic group; 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) is selected from the compound of formula (I-D59):

[0223]

[0224] In some embodiments, the compound of formula (I-59) is selected from compounds of formula (I-E59):

[0225]

[0226] In some embodiments, the compound of formula (I-59) is selected from compounds of formula (ID-i59) or (ID-ii59):

[0227]

[0228] In some embodiments, the compound of formula (I-59) is selected from compounds of formula (IE-i59) or (IE-ii59):

[0229]

[0230] In some embodiments, the compound is:

[0231]

[0232]

[0233] In one aspect, provided herein are compounds according to formula (I-66):

[0234]

[0235] or a pharmaceutically acceptable salt thereof, wherein: R 1 is an alkyl group (e.g., a C1-C6 alkyl group); 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 are each independently hydrogen, halogen 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 , together with the carbon atom to which they are attached, form an oxo group; R 6 is absent or is hydrogen; and represents a single bond or a double bond, where When one of them is a double bond, the other is a single bond; when two When both are single bonds, then R 6 is hydrogen; and when When one of them is a double bond, R 6 Does not exist.

[0236] In some embodiments, R 1 is an alkyl group (eg, a C1-C6 alkyl group). 1 is C1-C6 alkyl (e.g., -CH3, -CH2CH3, -CH2OCH3, or -CF3). 1 is -CH3, -CF3 or -CH2CH3. In some embodiments, R 1 -CH2OR A , where R A is a C1-C6 alkyl group (e.g., a C1-C3 alkyl group).

[0237] 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).

[0238] In some embodiments, R 3 is hydrogen or alkyl (e.g., C1-C6 alkyl). 3 is hydrogen, unsubstituted alkyl (eg, unsubstituted C1-C6 alkyl), or halogenated alkyl (eg, -CF3).

[0239] In some embodiments, R 4 is -OH or halogen (eg, -F).

[0240] 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 halogen (e.g., -F). In some embodiments, R 4 and R 5 is halogen (e.g., -F). In some embodiments, R 4 and R 5 For hydrogen.

[0241] In some embodiments, R 2is aryl (e.g., substituted or unsubstituted aryl, for example, substituted or unsubstituted phenyl), heteroaryl (e.g., substituted or unsubstituted heteroaryl, for example, substituted or unsubstituted pyridyl), aralkyl (e.g., substituted or unsubstituted aralkyl, for example, substituted or unsubstituted benzyl), or heteroaralkyl and R 3 is hydrogen or alkyl (eg, unsubstituted C1-C6 alkyl, eg, C1-C6 haloalkyl). 2 is aryl (e.g., substituted or unsubstituted aryl, for example, substituted or unsubstituted phenyl), heteroaryl (e.g., substituted or unsubstituted heteroaryl, for example, substituted or unsubstituted pyridyl), aralkyl (e.g., substituted or unsubstituted aralkyl, for example, substituted or unsubstituted benzyl), or heteroaralkyl and R 3 is hydrogen, –CH3 or –CF3.

[0242] In some embodiments, R 1 is an alkyl group (e.g., a C1-C6 alkyl group), R 2 is aryl (e.g., substituted or unsubstituted aryl, for example, substituted or unsubstituted phenyl), heteroaryl (e.g., substituted or unsubstituted heteroaryl, for example, substituted or unsubstituted pyridyl), aralkyl (e.g., substituted or unsubstituted aralkyl, for example, substituted or unsubstituted benzyl), or heteroaralkyl, and R 3 is hydrogen, -CH3 or -CF3. In some embodiments, R 1 is –CH3 or –CH2CH3, R 2 is unsubstituted phenyl, unsubstituted pyridyl, or unsubstituted benzyl, and R 3 is hydrogen, –CH3 or –CF3.

[0243] In some embodiments, the compound of formula (I-66) is selected from compounds of formula (I-A66), (I-B66), or (I-C66):

[0244]

[0245] In some embodiments, the compound of formula (I-66) is selected from compounds of formula (I-A66):

[0246]

[0247] In some embodiments, the compound is:

[0248]

[0249]

[0250] In one aspect, provided herein are compounds according to formula (I-61):

[0251]

[0252] or a pharmaceutically acceptable salt thereof, wherein: R 1 is hydrogen or alkyl (e.g., C1-C6 alkyl); R 2 and R 3 Each is independently hydrogen, alkyl, aryl, heteroaryl, carbocyclic or heterocyclic or R 2 and R 3 , together with the carbon atoms to which they are attached, form a 3-8 membered ring; R 4 and R 5 are each independently hydrogen, halogen or -OR C , where R C is hydrogen or alkyl (e.g., C1-C6 alkyl), or R 4 and R 5 , together with the carbon atom to which they are attached, form an oxo group; R 6 is absent or is hydrogen; and represents a single bond or a double bond, where When one of them is a double bond, the other is a single bond; when two When both are single bonds, then R 6 is hydrogen; and when When one of them is a double bond, R 6 Does not exist; provided that the following compounds are not included:

[0253] In some embodiments, R 1 is alkyl (e.g., C1-C6 alkyl) or hydrogen. 1 is C2-C6 alkyl (e.g., C3-C6 alkyl) or hydrogen. In some embodiments, R 1 is substituted or unsubstituted C2-C6 alkyl (e.g., substituted or unsubstituted C3-C6 alkyl) or hydrogen. 1 is methyl or ethyl (eg, substituted or unsubstituted methyl or substituted or unsubstituted ethyl). In some embodiments, R 1 is a substituted or unsubstituted methyl or a substituted or unsubstituted ethyl. 1 In some embodiments, R 1 -CH2OR A , where R A is a C1-C6 alkyl group (e.g., a C1-C3 alkyl group).

[0254] In some embodiments, R2 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). 2 In some embodiments, R 2 is isopropyl (eg, substituted or unsubstituted isopropyl). In some embodiments, R 2 is substituted or unsubstituted isopropyl. 2 is a haloalkyl group (eg, a C1-C6 haloalkyl group).

[0255] In some embodiments, R 2 and R 3 Each is independently alkyl (e.g., C1-C6 alkyl) or hydrogen. 2 and R 3 Each 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 3-8 membered ring. In some embodiments, R 2 and R 3 Each is independently hydrogen or C1-C6 alkyl (e.g., C2-C6 alkyl). 2 and R 3 are each independently hydrogen or substituted or unsubstituted C1-C6 alkyl, (eg, substituted or unsubstituted C2-C6 alkyl). 2 and R 3 Each is independently hydrogen or C3-C6 alkyl (e.g., isopropyl). 2 and R 3 Each is independently hydrogen or a substituted or unsubstituted C3-C6 alkyl group (eg, a substituted or unsubstituted isopropyl group).

[0256] In some embodiments, R 4 is -OH or halogen (eg, -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 halogen (e.g., -F). In some embodiments, R 4 and R 5 is halogen (e.g., -F). In some embodiments, R 4 and R 5For hydrogen.

[0257] In some embodiments, R 2 and R 3 In some embodiments, R 2 is a C1-C6 alkyl group and R 3 is a C2-C6 alkyl group (e.g., a C3-C6 alkyl group). 2 is a substituted or unsubstituted C1-C6 alkyl group and R 3 is a substituted or unsubstituted C2-C6 alkyl group (eg, a substituted or unsubstituted C3-C6 alkyl group). 1 is ethyl (eg, substituted or unsubstituted ethyl) and R 2 and R 3 is methyl (eg, substituted or unsubstituted methyl). In some embodiments, R 1 is a substituted or unsubstituted ethyl group and R 2 and R 3 is a substituted or unsubstituted methyl group. 1 is ethyl, R 2 is isopropyl, and R 3 In some embodiments, R 1 is a substituted or unsubstituted ethyl group, R 2 is a substituted or unsubstituted isopropyl group, and R 3 In some embodiments, R 1 is ethyl, R 2 is isopropyl, and R 3 In some embodiments, R 1 is a substituted or unsubstituted ethyl group, R 2 is a substituted or unsubstituted isopropyl group, and R 3 is a substituted or unsubstituted methyl group.

[0258] In some embodiments, the compound of formula (I-61) is a compound of formula (I-A61), (I-B61), or (I-C61):

[0259]

[0260] In some embodiments, the compound of formula (I-61) is selected from compounds of formula (I-C61):

[0261]

[0262] In some embodiments, the compound of formula (I-61) is selected from compounds of formula (I-A61):

[0263]

[0264] In some embodiments, the compound of formula (I-61) is selected from compounds of formula (IC-i61) or (IC-ii61):

[0265]

[0266] In some embodiments, the compound is:

[0267]

[0268] In one aspect, the present invention relates to compounds of formula (I-62):

[0269]

[0270] or a pharmaceutically acceptable salt thereof, wherein: R 1 is hydrogen or alkyl (e.g., C1-C6 alkyl); R 2 and R 3 Each is independently hydrogen, alkyl, carbocyclic or heterocyclic or R 2 and R 3 , together with the carbon atoms to which they are attached, form a 3-8 membered ring; R 4 and R 5 are each independently hydrogen, halogen or -OR C , where R C is hydrogen or alkyl (e.g., C1-C6 alkyl), or R 4 and R 5 , together with the carbon atom to which they are attached, form an oxo group; R 6 is absent or is hydrogen; and represents a single bond or a double bond, where When one of them is a double bond, the other is a single bond; when two When both are single bonds, then R 6 is hydrogen; and when When one of them is a double bond, R 6 Does not exist.

[0271] In some embodiments, R 1 is an alkyl group (eg, a C1-C6 alkyl group). 1 is a substituted or unsubstituted C2-C6 alkyl group (eg, a substituted or unsubstituted C3-C6 alkyl group). 1 is methyl or ethyl (eg, substituted or unsubstituted methyl or substituted or unsubstituted ethyl). In some embodiments, R 1 is a substituted or unsubstituted methyl or a substituted or unsubstituted ethyl. 1In some embodiments, R 1 -CH2OR A , where R A is a C1-C6 alkyl group (e.g., a C1-C3 alkyl group).

[0272] 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). 2 is a haloalkyl group (eg, a C1-C6 haloalkyl group).

[0273] In some embodiments, R 2 and R 3 Each is independently hydrogen or C1-C6 alkyl (e.g., C2-C6 alkyl). 2 and R 3 are each independently hydrogen or substituted or unsubstituted C1-C6 alkyl (eg, substituted or unsubstituted C2-C6 alkyl). 2 and R 3 Each is independently alkyl (e.g., C1-C6 alkyl) or hydrogen. 2 and R 3 Each 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 3-8 membered ring.

[0274] In some embodiments, R 4 is -OH or halogen (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 halogen (e.g., -F). In some embodiments, R 4 and R 5 is halogen (e.g., -F). In some embodiments, R 4 and R 5 For hydrogen.

[0275] In some embodiments, R 1 is ethyl (eg, substituted or unsubstituted ethyl) and R 2 and R 3is methyl (eg, substituted or unsubstituted methyl). In some embodiments, R 1 is a substituted or unsubstituted ethyl group and R 2 and R 3 is a substituted or unsubstituted methyl group.

[0276] In some embodiments, the compound of formula (I-62) is a compound of formula (I-A62), (I-B62), or (I-C62):

[0277]

[0278]

[0279] In some embodiments, the compound of formula (I-62) is selected from compounds of formula (I-C62):

[0280]

[0281] In some embodiments, the compound of formula (I-62) is selected from compounds of formula (I-A62):

[0282]

[0283] In some embodiments, R 1 is ethyl (eg, substituted or unsubstituted ethyl) and R 2 and R 3 is methyl (eg, substituted or unsubstituted methyl). In some embodiments, R 1 is a substituted or unsubstituted ethyl group and R 2 and R 3 is a substituted or unsubstituted methyl group.

[0284] In some embodiments, the compound of formula (I-62) is selected from compounds of formula (IC-i62) or (IC-ii62):

[0285]

[0286] In some embodiments, the compound is

[0287]

[0288] In one aspect, provided herein are compounds according to formula (I-60):

[0289]

[0290] or a pharmaceutically acceptable salt thereof, wherein: R 2 and R 3are each independently hydrogen, alkyl (e.g., C1-C6 alkyl), carbocyclyl, heterocyclyl, aryl or heteroaryl, or R 2 and R 3 , together with the carbon atoms to which they are attached, form a 3-8 membered ring; R 4 and R 5 are each independently hydrogen, halogen or –OR C , where R C is hydrogen or alkyl (e.g., C1-C6 alkyl), or R 4 and R 5 , together with the carbon atom to which they are attached, form an oxo group; R 6 is absent or is hydrogen; and represents a single bond or a double bond, where When one of them is a double bond, the other is a single bond; when two When both are single bonds, then R 6 is hydrogen; and when When one of them is a double bond, R 6 Does not exist.

[0291] In some embodiments, R 2 is alkyl (e.g., C1-C6 alkyl) or hydrogen. 2 is a haloalkyl group (eg, a C1-C6 haloalkyl group). 2 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl) or hydrogen. 2 is an aryl group or a heteroaryl group.

[0292] In some embodiments, R 2 and R 3 Each is independently alkyl (e.g., C1-C6 alkyl) or hydrogen. 2 and R 3 Each is independently substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl) or hydrogen. 2 and R 3 Each is independently unsubstituted alkyl (e.g., unsubstituted C1-C6 alkyl) or hydrogen. 2 and R 3 Each is independently C1-C6 haloalkyl (e.g., trifluoromethyl) or hydrogen. In some embodiments, R 2 and R 3 Each is independently aryl or heteroaryl. In some embodiments, R 2 and R 3 , together with the carbon atom to which they are attached, form a 3-membered ring.

[0293] 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 3-8 membered carbocyclic or heterocyclic ring.

[0294] In some embodiments, R 2 is a carbocyclic or heterocyclic group and R 3 In some embodiments, R 2 is trifluoromethyl and R 3 In some embodiments, R 2 is an aryl or heteroaryl group and R 3 In some embodiments, R 2 and R 3 is methyl (eg, substituted or unsubstituted methyl). In some embodiments, R 2 and R 3 In some embodiments, R 2 and R 3 is an unsubstituted methyl group.

[0295] In some embodiments, R 4 is -OH or halogen (eg, -F). In some embodiments, R 4 and R 5 , together with the carbon atom to which they are attached, form an oxo group.

[0296] In some embodiments, R 4 is hydrogen and R 5 is halogen (e.g., -F). In some embodiments, R 4 and R 5 is halogen (e.g., -F). In some embodiments, R 4 and R 5 For hydrogen.

[0297] In some embodiments, the compound of formula (I-60) is selected from compounds of formula (I-A60), (I-B60), or (I-C60):

[0298]

[0299] In some embodiments, the compound of formula (I-60) is selected from compounds of formula (I-B60):

[0300]

[0301] In some embodiments, R2 and R 3 At least one of them is C1-C6 alkyl, carbocyclic group, heterocyclic group, aryl or heteroaryl; or R 2 and R 3 , together with the carbon atoms to which they are attached, form a 3-8 membered ring.

[0302] In some embodiments, R 2 is methyl and R 3 In some embodiments, R 2 is an unsubstituted methyl group and R 3 In some embodiments, R 2 and R 3 For hydrogen.

[0303] In some embodiments, the compound is:

[0304]

[0305] Alternative implementation plans

[0306] In an alternative embodiment, 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 may be, for example, 13 C or 14 C; oxygen may be, for example, 18 O; nitrogen may 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 in the compound.

[0307] Pharmaceutical composition

[0308] In another aspect, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of Formula 1-59, 1-66, 1-61, 1-62, or 1-60.

[0309] When used as a medicine, the compounds provided herein are generally administered in the form of a pharmaceutical composition. The composition can be prepared in a manner well known in the pharmaceutical field and contains at least one active compound.

[0310] In one embodiment, with respect to pharmaceutical compositions, the carrier is a parenteral carrier, oral or topical carrier.

[0311] The present invention also relates to compounds of formula 1-59, 1-66, 1-61, 1-62 or 1-60 or pharmaceutical compositions thereof, and their pharmaceutical or medicaments.

[0312] Typically, the compounds provided herein are administered in a therapeutically effective amount. The amount of the compound to be administered is typically determined by a physician based on the relevant circumstances (including the condition being treated, the route of administration selected, the compound actually administered, the age, weight, and response of each patient, the severity of the patient's symptoms, etc.).

[0313] The pharmaceutical compositions provided herein can be administered by various routes, including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal. Depending on the desired route of delivery, the compounds provided herein are preferably formulated as injectable or oral compositions, or as saline, lotions or patches for transdermal administration.

[0314] Compositions for oral administration can take the form of bulk liquid solutions or suspensions or bulk powders. However, more commonly, the composition exists in unit dosage form to aid accurate administration. The term "unit dosage form" refers to physically dispersed units suitable for single doses of human subjects and other mammals, each unit containing a predetermined amount of active substance and a suitable pharmaceutical excipient, wherein the amount of the active substance is calculated to produce the desired therapeutic effect. Typical unit dosage forms include ampoules or syringes of pre-filled, pre-measured liquid compositions, or pills, tablets, or capsules in the case of solid compositions. In the composition, the compound is typically a small component (about 0.1 to 50 wt % or preferably about 1 to about 40 wt %), with the remainder being various vehicles or carriers, and processing aids that contribute to the formation of the desired dosage form.

[0315] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle, as well as buffers, suspending and dispersing agents, colorants, flavorings, etc. Solid forms may include, for example, any of the following ingredients or compounds having similar properties: binders such as microcrystalline cellulose, tragacanth, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as mint, methyl salicylate, or orange flavor.

[0316] Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline or other injectable carriers known in the art. As previously described, the active compound in the composition is typically a minority component, typically about 0.05 to 10% by weight, with the remainder being an injectable carrier, etc.

[0317] Transdermal compositions are usually formulated as topical ointments or creams containing active ingredients, and the amount of the active ingredient is usually about 0.01 to about 20 weight %, preferably about 0.1 to about 20 weight %, preferably about 0.1 to about 10 weight %, and more preferably about 0.5 to about 15 weight %. When formulated as an ointment, the active ingredient is usually combined with paraffin or a water-miscible ointment base. Alternatively, the active ingredient can be formulated as an emulsifiable paste together with, for example, an oil-in-water cream base. This transdermal preparation is known in the art and usually includes other ingredients to increase the transdermal penetration stability of the active ingredient or preparation. All of these known transdermal preparations and ingredients are included within the scope as described herein.

[0318] The compounds provided herein can also be administered via transdermal devices. Thus, transdermal administration can be accomplished through the use of patches of the reservoir or porous membrane type or through the use of solid matrix types.

[0319] The ingredients for orally administrable, injectable or topically administrable compositions described above are representative only. Additional materials and processing techniques are listed in Section 8 of Remington's Spharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0320] The ingredients for orally administrable, injectable or topically administrable compositions are merely representative. Additional materials and processing techniques are listed in Section 8 of Remington's The Science and Practice of Pharmacy, 21 edition, 2005, publisher: Lippincott Williams & Wilkins, which is incorporated herein by reference.

[0321] The compounds of the present invention can be administered in a sustained release form or by a sustained release drug delivery system. A description of representative sustained release materials can be found in Remington's Spharmaceutical Sciences.

[0322] 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 comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β- and γ-cyclodextrins, which are composed of 6, 7 and 8 α-l,4-linked glucose units, respectively, optionally containing one or more substituents on the linked sugar portion, including but not limited to methylation, hydroxyalkylation, acylation and sulfoalkyl ether substituents. In some embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, such as, for example, sulfobutyl ether β-cyclodextrin, also known as See, for example, US Pat. No. 5,376,645. In some embodiments, the formulation comprises hexapropyl-β-cyclodextrin. In more specific embodiments, the formulation comprises hexapropyl-β-cyclodextrin (10-50% in water).

[0323] 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 pharmaceutically acceptable anions, such as hydrochlorides, hydroiodides, hydrobromides, nitrates, sulfates, bisulfates, phosphates, acetates, lactates, citrates, tartrates, succinates, maleates, fumarates, benzoates, p-toluenesulfonates, and the like.

[0324] The following formulation examples illustrate representative pharmaceutical compositions that can be prepared according to the present invention. However, the present invention is not limited to the following pharmaceutical compositions.

[0325] 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 mixed as a dry powder with a dry gelatin binder in a weight ratio of about 1:2. A small amount of magnesium stearate can be added as a lubricant. The mixture is formed into 240 to 270 mg tablets (each tablet having 80 to 90 mg of active compound) in a tablet press.

[0326] 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 a weight ratio of about 1: 1. The mixture is filled into 250 mg capsules (each capsule having 125 mg of active compound).

[0327] Exemplary preparation 3-liquid: Formula I-59, I-66, I-61, I-62 or I-60 compound or its pharmaceutically acceptable salt (125mg) can be mixed with sucrose (1.75g) and xanthan gum (4mg), and the resulting mixture can be blended, sieved with 10 mesh US sieves, and then mixed with the aqueous solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50mg) prepared before this. Sodium benzoate (10mg), flavoring and coloring agent are diluted with water and added under stirring.Sufficient water can then be added to produce a cumulative volume of 5mL.

[0328] 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 mixed as a dry powder with a dry gelatin binder in a weight ratio of about 1:2. A small amount of magnesium stearate can be added as a lubricant. The mixture is formed into 450 to 900 mg tablets (150 to 300 mg of active compound) in a tablet press.

[0329] Exemplary Formulation 5 - Injection: A compound of Formula 1-59, 1-66, 1-61, 1-62 or 1-60, or a pharmaceutically acceptable salt thereof, can be dissolved in a buffered sterile saline injectable aqueous medium or suspended in a buffered sterile saline injectable aqueous medium at a concentration of about 5 mg / mL.

[0330] 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 mixed as a dry powder with a dry gelatin binder in a weight ratio of about 1:2. A small amount of magnesium stearate can be added as a lubricant. The mixture is formed into 90 to 150 mg tablets (30 to 50 mg of active compound per tablet) on a tablet press.

[0331] 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 mixed as a dry powder with a dry gelatin binder in a weight ratio of about 1:2. A small amount of magnesium stearate can be added as a lubricant. The mixture is formed into 30 to 90 mg tablets (10 to 30 mg of active compound per tablet) on a tablet press.

[0332] 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 mixed as a dry powder with a dry gelatin binder in a weight ratio of about 1:2. A small amount of magnesium stearate can be added as a lubricant. The mixture is formed into 0.3 to 30 mg tablets (0.1 to 10 mg of active compound per tablet) on a tablet press.

[0333] 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 mixed as a dry powder with a dry gelatin binder in a weight ratio of about 1:2. A small amount of magnesium stearate can be added as a lubricant. The mixture is formed into 150 to 240 mg tablets (50 to 80 mg of active compound per tablet) in a tablet press.

[0334] 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 mixed as a dry powder with a dry gelatin binder in a weight ratio of about 1:2. A small amount of magnesium stearate can be added as a lubricant. The mixture is formed into 270 to 450 mg tablets (90 to 150 mg of active compound per tablet) on a tablet press.

[0335] The injected dose level is in the range of about 0.1 mg / kg / hour to at least 10 mg / kg / hour over a period of about 1 hour to 120 hours, and more particularly over a period of 24 to 96 hours. A preload bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady-state levels. For a 40 to 80 kg human patient, the total maximum dose is expected to not exceed about 2 g / day.

[0336] In order to prevent and / or treat long-term conditions, treatment regimens are typically extended to many months or years, so oral administration is preferred, taking into account the patient's convenience and tolerance. For oral administration, 1 to 5 times a day, especially 2 to 4 times a day, and typically 3 oral doses a day are representative regimens. Using these dosage regimens, each dose provides about 0.01 to about 20 mg / kg of the compounds of this invention, preferably about 0.1 to about 10 mg / kg, and especially about 1 to about 5 mg / kg.

[0337] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injectable doses.

[0338] When used to avoid CNS disorders, the compounds provided herein are administered at the dosage levels described above to subjects at risk of developing the disorder, typically under the advice and supervision of a physician. Subjects at risk of developing a specific disorder typically include those with a family history of the disorder or those identified as being particularly susceptible to developing the disorder by genetic testing or screening.

[0339] Treatment and usage

[0340] The compounds of the present invention, for example, compounds of Formula 1-59, 1-66, 1-61, 1-62 or 1-60, and pharmaceutically acceptable salts thereof, as described herein, can be used in methods for achieving positive allosteric modulation of PMDA receptors in a subject in need thereof, comprising administering to a subject a compound that achieves negative allosteric modulation of an NMDA receptor in a subject in need thereof, comprising administering to a subject a compound of the general formula.

[0341] The compounds of the present invention, for example, 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 to treat and prevent, for example, CNS-related disorders in a subject. In some embodiments, the compounds described herein, for example, 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 described herein, refers to, for example, inhibition or enhancement of NMDA receptor function. In certain embodiments, the compounds of formula I-59, I-66, I-61, I-62 or I-60, or pharmaceutically acceptable salts thereof, act as negative allosteric modulators (NAMs) of NMDA and inhibit NMDA receptor function. In certain embodiments, the compounds described herein, for example, compounds of formula I-59, I-66, I-61, I-62 or I-60, or pharmaceutically acceptable salts thereof, act as positive allosteric modulators (PAMs) of NMDA and enhance NMDA receptor function. In certain embodiments, compounds of formula I-59, I-66, I-61, I-62 or I-60, or pharmaceutically acceptable salts thereof, block or reduce the enhancement or inhibition of NMDA receptor function by naturally occurring substrates. Such compounds do not act as negative allosteric modulators (NAMs) or positive allosteric modulators (PAMs) of NMDA. In some embodiments, the disease is cancer. In some embodiments, the disease is diabetes. In some embodiments, the disease is a sterol synthesis disorder. In some embodiments, the disease is a gastrointestinal (GI) disorder, e.g., constipation, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) (e.g., ulcerative colitis, Crohn's disease), structural disorders affecting the gastrointestinal tract, anal disorders (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas), colon polyps, cancer, or colitis. In some embodiments, the disease is inflammatory bowel disease.

[0342] Exemplary disorders 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 tract, anal disorders (e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids, anal fissures, perianal abscesses, anal fistulas), colon polyps, cancer, colitis, and CNS disorders, e.g., those described herein.

[0343] Exemplary disorders associated with NMDA-modulation (e.g., CNS disorders) include, but are not limited to, adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, social phobia, generalized anxiety disorder), cognitive disorders (including Alzheimer's disease and other forms of dementia including 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 disorder), sleep disorders (including insomnia), substance abuse-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those associated with Shank family proteins (including Shank3 ), neurodevelopmental disorders (including Rett syndrome), multiple sclerosis, sterol synthesis disorders, Smith-Lemli-Opitz syndrome, pain (including acute pain, chronic pain, and neuropathic pain), epilepsy (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 titers of anti-NMDA receptor antibodies (including anti-NMDA receptor encephalitis), neurodegenerative diseases, neuroinflammation, neuropsychiatric lupus, Niemann-Pick C disorder, and tinnitus.

[0344] In certain embodiments, the compounds of the invention, for example, compounds of Formula 1-59, 1-66, 1-61, 1-62, or 1-60, or pharmaceutically acceptable salts thereof, can be used to induce sedation or anesthesia.

[0345] In certain embodiments, compounds of Formula I-59, I-66, I-61, I-62 or I-60, or pharmaceutically acceptable salts thereof, are useful for treating or preventing 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 disorder), sleep disorders (including insomnia), substance abuse-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those associated with Shank family history of dementia). The present invention also includes the following diseases: those disorders associated with mutations in family proteins (including Shank3)), neurodevelopmental disorders (including Rett syndrome), multiple sclerosis, sterol synthesis disorders, Smith-Lemli-Opitz syndrome, pain (including acute pain, chronic pain, and neuropathic pain), epilepsy (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 titers of anti-NMDA receptor antibodies (including anti-NMDA receptor encephalitis), neurodegenerative diseases, neuroinflammation, neuropsychiatric lupus, Niemann-Pick C disorder, and tinnitus.

[0346] In certain embodiments, compounds of Formula I-59, I-66, I-61, I-62 or I-60, or pharmaceutically acceptable salts thereof, are useful for treating or preventing 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 disorder), personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those associated with mutations in Shank family proteins (including Shank3)), or postpartum psychosis.

[0347] In certain embodiments, compounds of Formula 1-59, 1-66, 1-61, 1-62 or 1-60, or pharmaceutically acceptable salts thereof, are useful for treating or preventing neurodevelopmental disorders (including Rett syndrome), multiple sclerosis, sterol synthesis disorders, Smith-Lemli-Opitz syndrome, pain (including acute pain, chronic pain, and neuropathic pain), epilepsy (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 titers of anti-NMDA receptor antibodies (including anti-NMDA receptor encephalitis), neurodegenerative diseases, neuroinflammation, neuropsychiatric lupus, Niemann-Pick C disorder, or tinnitus.

[0348] In some embodiments, compounds of the invention, e.g., compounds of Formula 1-59, 1-66, 1-61, 1-62, or 1-60 that are PAMs of NMDA receptor function, are useful for treating or preventing disorders (e.g., CNS-related disorders) including schizophrenia or other psychotic disorders (including schizoaffective disorder), sleep disorders (including insomnia), autism spectrum disorders (including those associated with mutations in Shank family proteins (including 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 of anti-NMDA receptor antibodies (including anti-NMDA receptor encephalitis).

[0349] In some embodiments, compounds of the invention, e.g., compounds of Formula 1-59, 1-66, 1-61, 1-62, or 1-60 that are NAMs of NMDA receptor function, are useful for treating or preventing disorders (e.g., CNS-related disorders) including anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, social phobia, generalized anxiety disorder), mood disorders (including depression (e.g., postpartum depression), bipolar disorder, dysthymic disorder, suicidality), personality disorders (including obsessive-compulsive personality disorder), neurodevelopmental disorders (including Rett syndrome), pain (including acute and chronic pain), epilepsy (including status epilepticus and monogenic forms of epilepsy such as Dravet disease and tuberous sclerosis complex (TSC)), stroke, traumatic brain injury, adjustment disorders, neuropsychiatric lupus, and tinnitus.

[0350] In some embodiments, compounds of the invention, e.g., compounds of Formula 1-59, 1-66, 1-61, 1-62, or 1-60 that function as PAMs or NAMs of NMDA receptors, are useful in treating or preventing disorders (e.g., CNS-related disorders) 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.

[0351] In another aspect, a method for treating or preventing brain excitability in a subject susceptible to or suffering from a condition associated with brain excitability is provided, comprising administering to the subject an effective amount 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.

[0352] In another aspect, the present invention provides a compound of the present invention, for example, a compound of formula I-59, I-66, I-61, I-62 or I-60, or a pharmaceutically acceptable salt thereof, in combination with another pharmacologically active agent. The compounds provided herein can be administered as the sole active agent, or they can be administered in combination with other agents. Combination administration can be performed by any technique apparent to those skilled in the art, including, for example, separate, sequential, simultaneous, and alternating administration.

[0353] Movement disorders

[0354] Also described herein are methods for treating movement disorders. As used herein, "movement disorders" refers to a variety of diseases and disorders associated with hyperkinetic movement disorders and related muscle control abnormalities. Exemplary movement disorders include, but are not limited to, Parkinson's disease and Parkinson's symptom syndrome (specifically defined as bradykinesia), dystonia, chorea and Huntington's disease, ataxia, tremor (e.g., essential tremor), myoclonus and startle, tics and Tourette's syndrome, restless legs syndrome, stiff-person syndrome, and gait disorders.

[0355] A tremor is an involuntary, sometimes rhythmic, contraction and relaxation of muscles that may involve oscillations or twitching of one or more body parts (eg, hands, arms, eyes, face, head, vocal cords, trunk, legs). Tremor includes hereditary, degenerative, and idiopathic disorders, such as Wilson's disease, Parkinson's disease, and essential tremor, respectively; metabolic diseases (such as thyroid-parathyroid disease, liver disease, and hypoglycemia); peripheral neuropathies (associated with Charcot-Marie-Tooth disease, Roussy-Levy disease, diabetes, and complex regional pain syndrome); toxins (nicotine, mercury, lead, carbon monoxide, manganese, arsenic, toluene); drug-induced disorders (narcolepsy, tricyclic antidepressants, lithium, cocaine, alcohol, epinephrine, bronchodilators, theophylline, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychological disorders. Clinical tremor can be classified as physiologic tremor, augmented physiologic tremor, essential tremor syndrome (including classic essential tremor, essential orthostatic tremor, and task- and position-specific tremor), dystonic tremor, Parkinsonian tremor, cerebellar tremor, Holmes' tremor (rubrospinal 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, Parkinsonian tremor, physiologic tremor, psychogenic tremor, or rubrospinal tremor.

[0356] Cerebellar tremor or intention tremor is a slow, broad tremor of the limbs that occurs after purposeful movement.Cerebellar tremor is caused by a lesion or damage in the cerebellum resulting from, for example, a tumor, a stroke, a disease (e.g., multiple sclerosis, a genetic degenerative disorder).

[0357] Atypical tremors occur in people affected by dystonia, a movement disorder characterized by sustained, involuntary muscle contractions that cause twisting and repetitive movements and / or pain and unusual postures or positions. Atypical tremors can affect any muscle in the body. Atypical tremors occur irregularly and are usually relieved by complete rest.

[0358] Essential tremor, or benign essential tremor, is the most common type of tremor. Some essential tremors may be mild and non-progressive, and may be slowly progressive, starting on one side of the body but affecting both sides within three years. The hands are most commonly affected, but the head, voice, tongue, legs, and trunk may also be involved. The frequency of tremors may decrease as a person ages, but their severity may increase. High levels of emotion, stress, fever, physical exhaustion, or low blood sugar may trigger tremors and / or increase their severity. Symptoms typically evolve over time and may be visible and persistent after an attack.

[0359] Orthostatic tremor is characterized by rapid (e.g., greater than 12 Hz) rhythmic muscle contractions of the legs and trunk that occur immediately after standing. Cramps are felt in the thighs and legs, and patients may shake uncontrollably when asked to stand in one place. Orthostatic tremor can occur in patients with essential tremor.

[0360] Parkinson's disease tremor is caused by damage to structures in the brain that control movement. Parkinson's disease tremor is often a precursor to Parkinson's disease and is often seen as a "ball-rolling" movement of the hands. It can also affect the jaw, lips, legs, and trunk. The onset of Parkinson's disease tremor usually begins after age 60. The movement begins in one limb or side of the body and can progress to include the other side.

[0361] Physiological tremors can occur in normal subjects and are not clinically significant. They can be seen in all voluntary muscle groups. Physiological tremors can be caused by some drugs, alcohol withdrawal, or medical conditions including overactive thyroid and hypoglycemia. Tremors typically have a frequency of about 10 Hz.

[0362] Psychogenic or hysterical tremors can occur at rest or during postural or kinetic movements. People with psychogenic tremors may have conversion disorder or another psychiatric disorder.

[0363] Rubral tremor is characterized by a coarse, slow tremor that can occur at rest, in a certain position, and intentionally. The tremor is associated with a disorder that affects the red nucleus of the midbrain, typically an unusual stroke.

[0364] Parkinson's disease attacks dopamine-producing nerve cells in the brain. Symptoms include muscle stiffness, tremors, and changes in speech and gait. Parkinson's disease is characterized by tremors, bradykinesia, rigidity, and postural instability. Parkinson's disease shares the symptoms found in Parkinson's disease, but is a symptom complex rather than a progressive neurodegenerative disease.

[0365] Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions that cause abnormal, often repetitive movements or postures. Dystonic movements can be patterned, torsional, and tremorous. Dystonia is often initiated or exacerbated by voluntary movements and is associated with overflow muscle activation.

[0366] Chorea is a neurological disorder characterized by rapid, involuntary movements that usually affects the shoulders, hips, and face.

[0367] Huntington's disease is a genetic disorder that progressively weakens nerve cells in the brain. Symptoms include uncontrolled movements, clumsiness, and balance problems. Huntington's disease can also affect walking, speaking, and swallowing.

[0368] Ataxia refers to the loss of complete control of body movements and can affect the fingers, hands, arms, legs, flesh, speech, and eye movements.

[0369] Myoclonus and startle are responses to sudden and unexpected stimuli, which may be auditory, tactile, visual, or vestibular.

[0370] Tics are involuntary movements that are usually sudden, brief, repetitive, but non-rhythmic, that often mimic normal behavior and often occur outside the context of normal activities. Tics can be classified as motor or articulatory, with motor tics being associated with movement and articulatory tics being associated with sound. Tics can be characterized as simple or complex. For example, simple motor tics involve only a few muscles confined to a specific body part.

[0371] Tourette syndrome is a childhood-onset inherited neuropsychiatric disorder characterized by multiple motor tics and at least one articulatory tic.

[0372] Restless legs syndrome is a neurosensory movement disorder characterized by uncontrollable movement of the legs while at rest.

[0373] Stiff limb syndrome is a progressive movement disorder characterized by involuntary painful spasms and muscle stiffness, typically involving the lower back and legs. It typically causes a straight-leg gait with lumbar kyphosis. Characteristic abnormalities in EMG recordings and sequential motor unit activity of paraspinal axial muscles are often observed. Variants include "stiff limb syndrome," which produces focal stiffness, typically affecting the distal leg and foot.

[0374] Gait disorders are abnormalities in the way or style of walking that may result from neuromuscular, arthritic, or other physical changes. Gait is classified based on the system responsible for the abnormal movement and includes hemiplegic gait, diplegic gait, neuropathic gait, myopathic gait, parkinsonian gait, choreiform gait, ataxic gait, and sensory gait.

[0375] Mood disorders

[0376] The present invention also provides methods for treating mood disorders, such as clinical depression, postpartum depression or postpartum depression, peripartum depression, atypical depression, depressive depression, psychotic major depressive disorder, catatonic depression, seasonal affective disorder, dysthymia, double depression, depressive personality disorder, recurrent brief depressive disorder, minor depressive disorder, bipolar disorder or manic-depressive illness, depression caused by a chronic medical condition, refractory depression, intractable depression, suicidal tendencies, suicidal ideation, or suicidal behavior.

[0377] Clinical depression is also referred to as major depressive disorder, major depressive disorder (MDD), major depression, unipolar depression, unipolar disorder and recurrent depression, and refers to a mental disorder characterized by severe and lasting low mood and accompanied by low self-esteem and loss of interest in activities that are usually enjoyed or inability to experience happiness. Some individuals with clinical depression have difficulty sleeping, weight loss, and generally feel agitated and irritable. Clinical depression affects the feelings, thoughts and behavior of the subject and can lead to a variety of emotional and physical problems. Subjects with clinical depression may have trouble carrying out daily activities and feel as if life has no hope.

[0378] Postpartum depression (PND), also known as postpartum depression (PPD), refers to a type of clinical depression that strikes women after childbirth. Symptoms can include sadness, fatigue, changes in sleep and eating habits, loss of libido, crying spells, anxiety, and irritability. In some embodiments, PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein). In some embodiments, PND is refractory depression (e.g., refractory depression as described herein).

[0379] In some embodiments, subjects with PND also experience depression or symptoms of depression during pregnancy. This depression is referred to herein as perinatal depression. In embodiments, subjects experiencing perinatal depression have an increased risk of experiencing PND.

[0380] Atypical depression (AD) is characterized by emotional reactivity (e.g., abnormal loss of interest and motivation), significant weight gain, or increased appetite. Patients with AD may also experience excessive sleep or hypersomnia (hypersomnia), a feeling of heaviness in the limbs, and significant social impairment due to excessive sensitivity to perceived interpersonal rejection.

[0381] Depressive depression is characterized by loss of pleasure in most or all activities (anesthesia), unresponsiveness to pleasurable stimuli, depressed mood that is more pronounced than grief or loss, excessive weight loss, or excessive guilt.

[0382] Psychotic major depressive disorder (PMD) or psychotic depression refers to a major depressive episode, specifically of a depressive nature, in which the subject experiences psychotic symptoms such as delusions and hallucinations.

[0383] Catatonic depression refers to a severe depressive disorder that involves movement disorders and other symptoms. The subject may become mute and catatonic, and may be immobile or exhibit purposeless or bizarre movements.

[0384] Seasonal affective disorder (SAD) refers to a type of seasonal depression in which a subject has a seasonal pattern of depressive episodes that arrive in the fall or winter.

[0385] Dysthymia refers to a condition related to unipolar depression in which the same physical and cognitive problems are evident. It is distinct from major depressive disorder and tends to last longer (e.g., at least 2 years).

[0386] Double depression refers to periods of considerable depressed mood (dysthymia) lasting at least 2 years and separated by periods of major depression.

[0387] Depressive personality disorder (DPD) refers to a personality disorder with depressive features.

[0388] Recurrent brief depressive disorder (RBD) refers to a condition in which a subject experiences depressive episodes approximately once a month, with each episode lasting 2 weeks or less and usually less than 2-3 days.

[0389] Minor depressive disorder or minor depression is depression in which at least two symptoms are present for 2 weeks.

[0390] Bipolar disorder, or manic-depressive illness, causes extreme mood swings, including highs (mania or hypomania) and lows (depression). During periods of mania, the person may feel or appear unusually happy, energetic, or irritable. They often make reckless decisions. The need for sleep is often reduced. During periods of depression, there may be crying spells, poor eye contact, and a negative outlook on life. The risk of suicide over 20 years for those with the disorder is as high as 6%, and 30%-40% have engaged in self-harm. Other mental health problems, such as anxiety and substance use disorders, are often associated with bipolar disorder.

[0391] Depression caused by a chronic medical condition is depression caused by a chronic medical condition such as cancer or chronic pain, chemotherapy, chronic stress, etc.

[0392] Refractory depression refers to a condition in which a subject has been treated for depression but the symptoms have not improved. For example, antidepressants or psychological counseling (psychotherapy) are unable to alleviate the symptoms of depression in subjects with refractory depression. In some cases, the symptoms of subjects with refractory depression improve, but recur. Refractory depression occurs in patients with depression who are resistant to standard pharmacological treatments (including tricyclic antidepressants, MAOIs, SSRIs, and dual and triple uptake inhibitors and / or antianxiety medications) and non-pharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation, and / or transcranial magnetic stimulation).

[0393] Suicidal tendencies, suicidal ideation, and suicidal behavior refer to a subject's tendency to commit suicide. Suicidal ideation is associated with suicidal thoughts or unusual preoccupations with suicide. The scope of suicidal ideation varies widely, ranging from fleeting thoughts to extensive thoughts, detailed plans, role-playing, and incomplete attempts. Symptoms include talking about suicide, acquiring methods to commit suicide, social isolation, preoccupation with death, feelings of being trapped or hopeless about one's situation, increased alcohol or drug use, engaging in risky or self-destructive behaviors, and saying goodbye to people as if they were forever.

[0394] Symptoms of depression include persistent anxiety or sadness, helplessness, despair, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, physical challenges, loss of interest in pleasurable activities or hobbies, loss of concentration, loss of energy, low self-esteem, lack of positive thoughts or plans, excessive sleeping, overeating, loss of appetite, insomnia, self-harm, suicidal thoughts and suicide attempts. The presence, severity, frequency and duration of symptoms can vary based on individual case. Symptoms of depression and their relief can be determined by a doctor or psychologist (e.g., via a mental status examination).

[0395] anxiety disorders

[0396] This article provides methods for treating anxiety disorders. Anxiety disorders are an umbrella term that encompasses several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria can distinguish between a variety of anxiety disorders.

[0397] Generalized anxiety disorder (GAD) is a common, chronic condition characterized by a persistent state of anxiety and an inability to focus on any one object or situation. People with GAD experience persistent, nonspecific fear and worry and become excessively concerned with everyday events. GAD is the most common anxiety disorder affecting older adults.

[0398] In panic disorder, people experience temporary attacks of intense fear and apprehension, typically experiencing trembling, shaking, confusion, dizziness, nausea, and difficulty breathing. The APA defines these panic attacks as sudden onset of fear or discomfort that peaks within ten minutes and can last for several hours. These attacks can be triggered by stress, fear, or even exercise; however, the specific cause is not always obvious. In addition to recurrent, unexpected panic attacks, a diagnosis of panic disorder requires that the attacks have long-term consequences: worry about the possibility of an attack, persistent fear of future attacks, or significant changes in behavior associated with the attacks. Accordingly, people experiencing panic disorder experience symptoms that extend beyond the specific acute panic attack. Often, panic sufferers notice normal changes in their heartbeat, leading them to believe that their heart is malfunctioning or that they are about to have another panic attack. In some cases, during a panic attack, awareness of bodily functions is heightened (hyperarousal), with any noticeable physiological changes perceived as potentially life-threatening (i.e., extreme paranoia).

[0399] Obsessive-compulsive disorder is a type of anxiety disorder characterized by repetitive obsessions (distressing, persistent, and intrusive thoughts or images) and compulsions (the urge to perform specific actions or habits). OCD thought patterns can be somewhat likened to superstitions, involving a belief in a causal relationship that does not actually exist. Often, the process is completely illogical; for example, a compulsion may involve adopting a specific walking pattern to alleviate an obsession that threatens harm. In many cases, the compulsions are completely inexplicable and are simply a compulsion to complete a neurologically triggered habit. In rare cases, people with OCD may experience only obsessions without obvious compulsions; even more rarely, people experience only obsessions.

[0400] The single largest type of anxiety disorder is phobia, which includes all cases of fear and anxiety triggered by a specific stimulus or situation. The patient begins by encountering the target of their fear, which can be anything from an animal to a place to a bodily fluid, typically anticipating a phobic outcome.

[0401] Post-traumatic stress disorder, or PTSD, is an anxiety disorder that results from a traumatic experience. Post-traumatic stress can result from extreme situations, such as combat, rape, hostage-taking, or even serious accidents. It can also result from prolonged exposure to severe stressors, such as soldiers who can tolerate a single combat situation but cannot cope with continuous combat. Common symptoms include flashbacks, avoidance behavior, and depression.

[0402] epilepsy

[0403] Epilepsy is a brain disorder characterized by recurring seizures over time. Types of epilepsy may include, but are not limited to, generalized epilepsy, such as petit mal epilepsy of childhood, juvenile myoclonic epilepsy, grand mal seizures on awakening, West syndrome, petit mal myoclonic dysraphism, partial epilepsy, such as psychomotor epilepsy, frontal lobe epilepsy, and benign focal epilepsy of childhood.

[0404] Epilepsy

[0405] Epileptogenesis is a progressive process by which a normal brain develops epilepsy (a chronic condition characterized by seizures). Epileptogenesis is caused by cumulative neuronal damage following an initial insult (e.g., status epilepticus).

[0406] Status epilepticus (SE)

[0407] Status epilepticus (SE) can include, for example, convulsive status epilepticus, such as early status epilepticus, complete status epilepticus, refractory status epilepticus, and super-refractory status epilepticus; non-convulsive status epilepticus, such as generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic unilateral (sexual) epileptic discharges. Convulsive status epilepticus is characterized by the presence of seizures with convulsive status epilepticus and can include early status epilepticus, definite status epilepticus, refractory status epilepticus, and super-refractory status epilepticus. Early status epilepticus can be treated with first-line therapy. Complete status epilepticus is characterized by status epilepticus attacks that continue despite treatment with first-line and second-line therapies. Refractory status epilepticus is characterized by status epilepticus attacks that continue despite treatment with first-line and second-line therapies, and is usually treated with general anesthesia. Ultra-refractory status epilepticus is characterized by persistent seizures lasting 24 hours or longer despite treatment with first-line therapies, second-line therapies, and general anesthesia.

[0408] Non-convulsive status epilepticus can include, for example, focal non-convulsive status epilepticus, such as complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, mild non-convulsive status epilepticus, generalized non-convulsive status epilepticus, such as tardive absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus.

[0409] epileptic seizures

[0410] An epileptic seizure is a physical finding or behavioral change that occurs after an episode of abnormal electrical activity in the brain. The term "seizure" is often used interchangeably with "convulsion." A convulsion occurs when a person's body shakes rapidly and uncontrollably. During a convulsion, a person's muscles repeatedly contract and relax.

[0411] Based on the type of behavior and brain activity, epileptic seizures are divided into two broad categories: generalized and partial (also called localized or focal) seizures. This classification of seizure types helps doctors diagnose whether a patient has epilepsy.

[0412] A generalized seizure is caused by electrical impulses that spread throughout the entire brain, while a partial seizure is caused by electrical impulses that are confined (at least initially) to a relatively small part of the brain. The part of the brain where the seizure occurs is sometimes called the focus.

[0413] There are six types of generalized epileptic seizures. The most common and prominent, and therefore the most well-known, are generalized convulsions, also known as grand mal seizures. In this type of seizure, the patient loses consciousness and usually collapses. This loss of consciousness is followed by a period of generalized body stiffness (called the "tonic" phase of the seizure) for 30 to 60 seconds, followed by a violent convulsion (the "clonic" phase) for 30 to 60 seconds, after which the patient falls into a deep sleep (the "postictal" or post-seizure phase). During a grand mal seizure, injuries and accidents may occur, for example, tongue biting and urinary incontinence.

[0414] Absence seizures cause a brief loss of consciousness (only a few seconds) with few or no symptoms. The patient (mostly children) typically stops moving and becomes dazed. These seizures begin and end suddenly and can occur several times a day. Patients are usually unaware that they are having a seizure, but they may be aware that they have "lost time."

[0415] Myoclonic seizures involve sporadic spasms, usually on both sides of the body. People sometimes describe the spasms as temporary electric shocks. When severe, these seizures can cause falls or unintentional throwing of objects.

[0416] Clonic seizures are repetitive, rhythmic spasms that involve both sides of the body at the same time.

[0417] A tonic seizure is characterized by muscle stiffening.

[0418] Atonic seizures involve a sudden and generalized loss of muscle tone, especially in the arms and legs, often resulting in falls.

[0419] Seizures described herein may include: epileptic seizures; acute repetitive seizures; clusters of seizures; continuous seizures; uninterrupted seizures; prolonged 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; gelastic seizures; generalized seizures; infantile spasms; focal seizures; large-scale bidirectional myoclonic seizures; multifocal seizures; neonatal seizures; nocturnal seizures; occipital lobe seizures; post-traumatic seizures; subtle seizures; Sylvan seizures; visual reflex seizures; or withdrawal spasms. In some embodiments, the seizure is a generalized seizure associated with Dravet syndrome, Lennox-Gastaut syndrome, tuberous sclerosis complex, Rett syndrome, or PCDH19 Female Pediatric Epilepsy.

[0420] abbreviation

[0421] 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-tert-butyl-4-methylphenolate; Me: methyl; i-Pr : isopropyl; t-Bu: tert-butyl; Ph: phenyl; Et: ethyl; Bz: benzoyl; BzCl: benzoyl chloride; CsF: cesium fluoride; DCC: dicyclohexylcarbodiimide; DCM: dichloromethane; DMAP: 4-dimethylaminopyridine; DMP: Dess-Martin periodinane; EtMgBr: ethylmagnesium bromide; EtOAc: ethyl acetate; TEA: triethylamine; AlaOH: alanine; Boc: tert-butoxycarbonyl. Py: pyridine; TBAF: tetra-n-butylammonium fluoride; THF: tetrahydrofuran; TBS: tert-butyldimethylsilyl; TMS: trimethylsilyl; TMSCF3: (trifluoromethyl)trimethylsilane; Ts: p-toluenesulfonyl; Bu: butyl;

[0422] Ti(OiPr)4: titanium tetraisopropoxide; LAH: lithium aluminum hydride; LDA: lithium diisopropylamide; LiOH.H2O: lithium hydroxide hydrate; MAD: methylaluminum di(2,6-di-tert-butyl-4-methylphenolate); MeCN: acetonitrile; NBS: N-bromosuccinimide; Na2SO4: sodium sulfate; Na2S2O3: sodium thiosulfate; PE: petroleum ether; MeCN: acetonitrile; MeOH: methanol; Boc: tert-butoxycarbonyl; MTBE: methyl tert-butyl ether; DMSO: dimethyl sulfoxide; DMF: N,N-dimethylformamide; 9-BBN: 9-borabicyclo[3.3.1]nonane; MePPh3Br: bromo(methyl)triphenylphosphorane; MeMgBr: methylmagnesium bromide; MeLi: methyllithium; NaHCO3: sodium bicarbonate. Example

[0423] 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 should not be construed as limiting their scope in any manner.

[0424] Unless otherwise stated, the stereochemistry specified herein (e.g., assigning "R" or "S" to the C24 position of a steroid) can be assigned tentatively (e.g., randomly). For example, when the absolute configuration is "S," the C24 position can be drawn in the "R" configuration. When the absolute configuration is "R," the C24 position can also be drawn in the "S" configuration.

[0425] The absolute configuration of the asymmetric center can be determined using methods known to those skilled in the art. In some embodiments, the absolute configuration of the 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 the asymmetric center elucidated by the X-ray crystal structure of the compound can be used to infer the absolute configuration of the corresponding asymmetric center in another compound obtained from the same or similar synthetic method ... compare with spectroscopic techniques (e.g., NMR spectroscopy, e.g., 1 H NMR spectroscopy or 19 F NMR spectroscopy) in combination with inferring the absolute configuration of a corresponding asymmetric center in another compound.

[0426] Materials and methods

[0427] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It should be understood that when typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, other processing conditions may also be used unless otherwise stated. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by conventional optimization by those skilled in the art.

[0428] In addition, it will be apparent to those skilled in the art that conventional protecting groups may be required to prevent undesirable reactions of specific functional groups. The selection of suitable protecting groups for specific functional groups and suitable conditions for protection and deprotection are known in the art. For example, various protecting groups and their introduction and removal are described in TW Greene and PGM Wuts, Protecting Groups in Organic Synthesis, 2nd edition, Wiley, New York, 1991, which is incorporated herein by reference.

[0429] 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 provided, which detail the preparation of representative oxysterols listed herein. The compounds provided herein can be prepared by one skilled in the art of organic synthesis from known or commercially available starting materials and reagents. Exemplary chiral columns that can be used to separate / purify the enantiomers / diastereomers provided herein include, but are not limited to, AD-10, OB, OB-H, OD, OD-H, OF OG, OJ and OK.

[0430] It should be understood that this paper reports 1 H-NMR (e.g., for the δ (ppm) region from about 0.5 to about 4 ppm) is an exemplary interpretation (e.g., exemplary peak integration) of the NMR spectrum of the compound. 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

[0431] Exemplary general method for analytical HPLC: Mobile phase: A: water (10 mM NH4HCO3), B: acetonitrile, gradient: 5%-95% B over 1.6 or 2 min; flow rate: 1.8 or 2 mL / min; column: XBridge C18, 4.6*50 mm, 3.5 μm@45C.

[0432] Exemplary General Method for SFC: Column: AD CSP (250mm*30mm, 10μm), gradient: 45% B, A=NH3H2O, B=MeOH, flow rate: 60mL / min. For example, AD_3_EtOH_DEA_5_40_25ML would indicate: "Column: Chiralpak AD-3 150×4.6mm ID, 3um mobile phase: A: CO2 B: Ethanol (0.05% DEA) Gradient: 5% to 40% B over 5 minutes and hold at 40% for 2.5 minutes, then hold 5% B for 2.5 minutes, flow rate: 2.5mL / min, column temperature: 35°C."

[0433] Example 1: NMDA potentiation

[0434] NMDA potentiation

[0435] Whole-cell patch clamp of mammalian cells (Ionworks Barracuda (IWB))

[0436] The effects of compounds on GluN1 / GluN2A glutamate receptors expressed in mammalian cells were investigated using whole-cell patch clamp techniques.

[0437] HEK293 cells were transformed with adenovirus 5 DNA and transfected with cDNA encoding human GRIN1 / GRIN2A genes. Stable transfectants were selected using G418 and anti-Zeocin genes incorporated into the expression plasmid, and selection pressure was maintained in the medium with G418 and Zeocin. 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.

[0438] The test article effects were evaluated in an 8-point concentration-response format (4 replicate wells / concentration). All test and control solutions contained 0.3% DMSO and 0.01% EL (C5135, Sigma). The test article formulation was loaded into a 384-well compound plate using an automated liquid handling system (SciClone ALH3000, Caliper LifeScienses). Measurements were performed using the Ion Works Barracuda platform according to the following procedures:

[0439] Electrophysiological procedures:

[0440] a) Intracellular solution (mM): 50 mM CsCl, 90 mM CsF, 2 mM MgCl2, 5 mM EGTA, 10 mM HEPES. Adjust to pH 7.2 with CsOH.

[0441] b) Extracellular solution, HB-PS (composition, in mM): NaCl, 137; KCl, 1.0; CaCl2, 5; HEPES, 10; glucose, 10; adjusted to pH 7.4 with NaOH (refrigerated before use).

[0442] c) Holding potential: -70 mV, potential during agonist / PAM application: -40 mV.

[0443] Recording Operations:

[0444] a) Extracellular buffer was loaded into the wells of the PPC plate (11 μL per well). Cell suspension was titrated into the wells of the PPC planar electrode (9 μL per well).

[0445] b) Whole-cell recordings were established via patch punches, where membrane currents were recorded using an on-board patch clamp amplifier.

[0446] c) Two recordings (scans) were performed. The first, during the pre-application of the test article alone (duration of pre-application - 5 min), the second, during the co-application of the test article and the agonist (EC 20 L-glutamate and 30 μM glycine) during the course of the experiment, thereby detecting the positive regulatory effect of the test article.

[0447] Test article was administered: the first pre-application consisted of adding 20 μL of a 2X concentration of test article solution, the second consisted of adding 20 μL of a 1X concentration of test article and 10 μL / s of agonist (total application time was 2 seconds).

[0448] Example 2: NAM and PAM

[0449] Whole-cell patch clamp of mammalian cells (Ionworks Barracuda (IWB))

[0450] The whole-cell patch clamp technique was used to investigate the positive allosteric modulatory activity of the test compounds on GluN1 / GluN2A and GluN2B glutamate receptors expressed in mammalian cells.

[0451] HEK293 cells were transformed with adenovirus 5 DNA and transfected with cDNA encoding human GRIN1 / GRIN2A genes. Stable transfectants were selected using G418 and anti-Zeocin genes incorporated into the expression plasmid, and selection pressure was maintained in the medium with G418 and Zeocin. 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.

[0452] The test article effects were evaluated in an 8-point concentration-response format (4 replicate wells / concentration). All test and control solutions contained 0.3% DMSO and 0.01% EL (C5135, Sigma). The test article formulation was loaded into a 384-well compound plate using an automated liquid handling system (SciClone ALH3000, Caliper LifeScienses). Measurements were performed using the Ion Works Barracuda platform according to the following procedures:

[0453] Electrophysiological procedures:

[0454] a) Intracellular solution (mM): 50 mM CsCl, 90 mM CsF, 2 mM MgCl2, 5 mM EGTA, 10 mM HEPES. Adjust to pH 7.2 with CsOH.

[0455] b) Extracellular solution, HB-PS (composition, in mM): NaCl, 137; KCl, 1.0; CaCl2, 5; HEPES, 10; glucose, 10; adjusted to pH 7.4 with NaOH (refrigerated before use).

[0456] c) Holding potential: -70 mV, potential during agonist / PAM application: -40 mV.

[0457] Recording Operations:

[0458] a) Extracellular buffer was loaded into the wells of the PPC plate (11 μL per well). Cell suspension was titrated into the wells of the PPC planar electrode (9 μL per well).

[0459] b) Whole-cell recordings were established via patch punches, where membrane currents were recorded using an on-board patch clamp amplifier.

[0460] c) Two recordings (scans) were performed. The first, during the pre-application of the test article alone (duration of pre-application - 5 min), the second, during the co-application of the test article and the agonist (EC 20 L-glutamate and 30 μM glycine) during the course of the experiment, thereby detecting the positive regulatory effect of the test article.

[0461] Test article was administered: the first pre-application consisted of adding 20 μL of a 2X concentration of test article solution, the second consisted of adding 20 μL of a 1X concentration of test article and 10 μL / s of agonist (total application time was 2 seconds).

[0462] Potentiation of channels by positive allosteric modulators (PAMs)

[0463] The potentiation of the channel by a positive allosteric modulator (PAM) will be calculated as

[0464] % activation = (I PAM / I EC10-30 )x100%-100%

[0465] Among them I PAM Will be L-glutamate EC 10-30 - the current induced in the presence of various concentrations of the test article, I EC20 L-glutamic acid EC 20 The average current induced.

[0466] The PAM concentration-response data will fit an equation of the following form:

[0467] % activation = % L-glutamate EC 20 +{(%MAX-%L-Glutamate EC 20 ) / [1+

[0468] ([Test] / EC 50 ) N ]},

[0469] where [test] would be the concentration of PAM (test article), EC 50 will be the concentration of PAM that produces half-maximal activation, N will be the Hill coefficient, and % L-glutamate EC 20 Will be L-glutamate EC 20 The percentage of the evoked current, %MAX, is the value of the EC value of L-glutamate. 20The percentage of current activated by the highest co-admitted PAM dose will be the percentage of current activated by the L-glutamate EC at each PAM concentration. 10-30 The percentage of current induced.

[0470] The maximum amplitude of the evoked current was measured and defined as the peak current amplitude (PCA).

[0471] Automated patch clamp system (QPatch HTX):

[0472] In this study, HEK 293 cells stably transfected with glutamate-activated GRIN1 / 2A isoform channels will be used with submaximal NMDA concentrations (300 μM NMDA, co-applied with 8 μM glycine) to investigate negative allosteric modulation by test compounds.

[0473] Cell culture

[0474] Typically, cells will be passaged at approximately 80% to 90% confluency. For electrophysiological measurements, cells will be harvested at approximately 80% to 90% confluency from sterile culture flasks containing complete culture medium. Cells will be transferred as a suspension in PBS to the QPatch 16X or QPatch HTX system for direct transfer to the centrifuge / washer.

[0475] Standard laboratory conditions: cells were cultured at 37°C in a humidified atmosphere containing 5% CO2 (relative humidity approximately 95%).

[0476] Culture medium: Cells will be 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.

[0477] Antibiotics: Complete medium as described above was supplemented with 100 μg / mL hygromycin, 15 μg / mL blasticidin, and 1 μg / mL puromycin.

[0478] Induction of expression: 2.5 μg / mL tetracycline was added 24 hours before the start of the experiment.

[0479] Dosage Formulation

[0480] Dose levels are based on the test compound provided. Vehicle is added to achieve a stock concentration of 10 mM (store at -10°C to 30°C). A separate stock solution of 1.0 mM is prepared in DMSO. Details of stock solution use (thawing, dose formulation) will be recorded in the raw data. The time period for stock solution use will be detailed in the report.

[0481] Test compound concentration

[0482] Dose levels are based on the test compound provided. Vehicle is added to achieve a stock concentration of 10 mM (store at -10°C to 30°C). A separate stock solution of 1.0 mM is prepared in DMSO. Details of stock solution use (thawing, dose formulation) will be recorded in the raw data. The time period for stock solution use will be detailed in the report.

[0483] A test concentration of 1.0 μM will be tested.

[0484] All test solutions will be prepared by diluting stock solutions with Mg-free bath solution alone or with Mg-free bath solution containing NMDA (300 μM) and glycine (8.0 μM) shortly before electrophysiological experiments and kept at room temperature (19° C. to 30° C.) when used. 0.1% DMSO will be used as a vehicle.

[0485] Frequency of Preparation: For each concentration tested, new test compound solutions will be prepared daily.

[0486] Stability of Dose Formulations: All preparation times will be recorded in the raw data. Any observations regarding test compound instability will be noted in the raw data.

[0487] Storage of Dosage Formulations: On the day of the experiment, the dosage formulations will be kept at room temperature (19°C to 30°C) until use.

[0488] bath lotion

[0489] To prepare for the experiment and form the Geohm seal, the following standard bath solutions will be used:

[0490] 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

[0491] 1x bath solution was prepared by diluting 10x bath solution without glucose and 100x glucose solution with water at least every 7 days. Both stock solutions were prepared before the start of the experiments in this study and stored at 1°C to 9°C (10x bath solution) or -10°C to -30°C (100x glucose solution). The batch number of the bath solution used in the experiment will be recorded in the raw data. When in use, the 1x bath solution will be kept at room temperature (19°C to 30°C). When not in use, the 1x bath solution will be stored at 1°C to 9°C.

[0492] After the Geo seal is formed, the following magnesium-free baths are used:

[0493] 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

[0494] Prepare this Mg-free bath as a 1x solution and store at 1° C. to 9° C. It will be prepared fresh at least every 10 days.

[0495] Intracellular solution

[0496] 1x intracellular solution will be thawed daily from frozen 1x intracellular solution that was prepared prior to the start of the experiments in this study, aliquoted, and stored at -10°C to -30°C. 1x intracellular solution will be kept at room temperature (19°C to 30°C) when in use. The remaining 1x intracellular solution will be stored in a refrigerator (1°C to 9°C). The 1x intracellular solution will include the components listed below:

[0497] Potassium chloride: 130 mM; Magnesium chloride: 1 mM; Mg-ATP: 5 mM; HEPES: 10 mM; EGTA: 5 mM; pH (KOH): 7.2

[0498] Cell processing

[0499] For this study, cells will be continuously perfused with NMDA / glycine, test compound, or test compound / NMDA / glycine.

[0500] In each case, a pre-wash step with the test compound of at least 30 seconds was performed between applications. For details, see Table A below.

[0501] Each experimental type will be analyzed in at least n=3 isolated cells. NMDA and glycine stock solutions will be prepared before the start of the experiments in this study and stored frozen (-10°C to -30°C) until the day of the experiment. Shortly before the electrophysiological experiment, the frozen stock solutions will be thawed and diluted.

[0502] Controls: The effects of vehicle (0.1% DMSO) and D-(-)-2-amino-5-phosphonopentanoic acid (AP-5) (100 μM) were measured in three cells every other week to ensure successful expression of NMDA receptors.

[0503] A 50 mM stock solution of AP-5 was prepared before the start of the experiments in this study, aliquoted, and stored frozen (-10°C to -30°C) until the day of the experiment. Shortly before the electrophysiological experiments, the frozen stock solution was thawed and then diluted in a Mg-free bath containing NMDA (300 μM) and glycine (8.0 μM) to give a final perfusion concentration of 100 μM.

[0504] Experimental procedures

[0505] The cells were transferred to the QPatch HTX system as a suspension in serum-free medium and maintained in a cell storage tank / stirrer during the experiment. All solutions applied to the cells, including intracellular solutions, were maintained at room temperature (19°C to 30°C).

[0506] In the sealing process, the above-mentioned standard bathing solution will be used.All solutions (including pipette solution) applied to cells will remain at room temperature (19 DEG C to 30 DEG C).After forming Gigaohm seal between the patch electrode and the independent HEK293 cells of transfection, only Mg-free bathing solution will be perfused and cell membrane will rupture to ensure that electricity enters the cell interior (full cell patch configuration).300 μM NMDA (and 8.0 μM glycine) are applied to the patch clamp cells after 5 seconds to measure inward current.Throughout the experiment, cells will be maintained at a holding potential of-80mV by voltage clamp.

[0507] For analysis of test compounds, NMDA receptors will be stimulated by 300 μM NMDA and 8.0 μM glycine and the test compound combinations described below. A thirty-second pre-wash step with the test compound will be performed between applications.

[0508] Table A: Application schedule; use dependency of test compounds

[0509]

[0510] Table B: Application scheme; control experiment

[0511]

[0512] Example 3. Synthesis of Compound 1.

[0513]

[0514] Step 1. To a mixture of MePPh Br (1.28 kg, 3.6 mol) in THF (4.5 L) was added t-BuOK (404 g, 3.6 mol) at 15 ° C under N . The resulting mixture was stirred at 50 ° C for 30 mins. Pregnenolone (950 g, 2.9 mol) was added in batches below 65 ° C. The reaction mixture was stirred at 50 ° C for 1 hour. The combined mixture was quenched with saturated NH 4 Cl aqueous solution (1 L) at 15 ° C. The THF layer was separated. The aqueous layer was extracted with EtOAc (2x2 L). The combined organic phases were concentrated in vacuo to obtain a solid. The solid was further purified by grinding with MeOH / H 2 O (1: 1, 15 L) under reflux to obtain A-1 (940 g, 99%), which was a solid.

[0515] 1 H NMR (400MHz, CDCl3) δ5.40-5.32 (m, 1H), 4.85 (s, 1H), 4.71 (s, 1H), 3.58-3.46 (m, 1H), 2.36-2.16 (m, 2H), 2.08-1. 94 (m, 2H), 1.92-1.62 (m, 9H), 1.61-1.39 (m, 6H), 1.29-1.03 (m, 4H), 1.01 (s, 3H), 0.99-0.91 (m, 1H), 0.59 (s, 3H).

[0516] Step 2. DMP (2.14 kg, 5.08 mol) was added portionwise to a solution of A-1 (800 g, 2.54 mol) in DCM (8 L) at 35 ° C. The reaction mixture was stirred at 35 ° C for 20 minutes. The reaction mixture was filtered. The filter cake was washed with DCM (3x1 L). The combined organic phase was washed with saturated Na2S2O3 / saturated NaHCO3 aqueous solution (3: 1, 2x1.5 L), brine (1.5 L), dried over Na2SO4, filtered and concentrated in vacuo to give A-2 (794 g, crude material) as a solid which was used directly in the next step.

[0517] Step 3. To a solution of TBAF (3.04mL, 1M in THF, 3.04mmol, Aldrich) in THF (100mL) was added TMSCF (25.8g, 182mmol), followed by a solution of A-2 (19g, 60.8mmol) in THF (100mL) at 0°C. The mixture was stirred at 0°C for 30mins. To the mixture was added TBAF (200mL, 1M in THF, 200mmol) at 0°C. The mixture was stirred for another 30mins at 0°C. Saturated NH4Cl aqueous solution (100mL) was added to the mixture and the mixture was concentrated in vacuo. PE / EtOAc (400mL, 1:1) was added to the residue, the organic layer was separated and merged with two other batches (2x10g of A-2). The combined organic layer was washed with water (300mL), brine (300mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain an oil. The residue is dissolved in DCM (150mL) and diluted with PE (750mL). The solution is poured into a silica gel column (500g, 100-200mesh) and eluted with PE:DCM:EtOAc=5:1:0.05 to 5:1:0.1 to obtain A-4 (12g, 17% yield) oily matter and impure A-3. Impure A-3 is recrystallized from MeCN (250mL) to obtain purified A-3 (6.5g), which is a solid. The A-3 recovered from the MeCN filtrate is subjected to silica gel chromatography (PE:DCM:EtOAc=50:1:1 to 20:1:1) to obtain a crude product, which is recrystallized from MeCN (20mL) to obtain purified A-3 (1g, 16% overall yield), which is a solid.

[0518] Note: A-3 and A-4 from 3 JH, identification of CF3 (FDCS). (J. Org. Chem. 2015, 80, 1754.).

[0519] A-3: 1 H NMR (400MHz, CDCl3) δ5.43-5.33 (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).

[0520] A-4: 1H NMR (400MHz, CDCl3) δ5.54-5.41 (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).

[0521] 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 h. The mixture was cooled to 0 ° C. EtOH (12 mL), NaOH (41.8 mL, 5 M, aq.) and H2O2 (20.9 mL, 10 M, aq.) were added dropwise to the mixture. The mixture was stirred at 50 ° C for 1 h and then cooled. Na2SO3 (100 mL, 25%, aq.) was added to the mixture. The mixture was extracted with EtOAc (300 mL). The organic layer was separated and purified by silica gel column (PE: EtOAc = 10: 1 to 5: 1) to obtain A-5 (7.1 g, 85%) as a solid.

[0522] 1 H NMR (400MHz, CDCl3) δ5.42-5.32 (m, 1H), 3.64 (dd, J=3.2, 10.4Hz, 1H), 3.37 (dd, J=6.8, 10.4Hz, 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).

[0523] 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. Water (100 mL) and EtOAc (200 mL) were added to the residue. 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 Na2SO4, filtered and concentrated in vacuo to obtain A-6 (9.8 g, 100%), which was a solid.

[0524] 1H NMR (400MHz, CDCl3) δ7.78 (d, J=8.0Hz, 2H), 7.34 (d, J=8.0Hz, 2H), 5.48-5.29 (m, 1H), 3.97 (dd, J=2.4, 9.2Hz, 1H), 3.77 ( dd, J=6.4, 9.2Hz, 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).

[0525] 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 this mixture was added PhSO2Na (0.93 g, 5.67 mmol). The mixture was stirred at 50 ° C for 2 hours. To this 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.

[0526] 1 H NMR (400MHz, CDCl3) δ7.98-7.87 (m, 2H), 7.70-7.52 (m, 3H), 5.39-5.31 (m, 1H), 3.14 (d, J=14.0Hz, 1H), 2.85 (dd, J=9.6 , 14.0Hz, 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).

[0527] Step 7. To a solution of i-Pr2NH (576 mg, 5.70 mmol) in THF (10 mL) was added n-BuLi (1.9 mL, 2.5 M in hexane, 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. A solution of 2-isopropyloxirane (245 mg, 2.85 mmol) in THF (2 mL) was added to the mixture at -70 ° C. The mixture was stirred at -70 ° C for 1 h, warmed to 10 ° C and stirred at 10 ° C for 16 hours. NH4Cl (5 mL, saturated aqueous solution) was added to the mixture. The mixture was extracted with EtOAc (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to obtain A-8 (1.2 g crude material), which was an oil.

[0528] Step 8. To a solution of A-8 (1.2 g, 1.96 mmol) in MeOH (60 mL) was added NiBr2 (5 mg, 0.023 mmol) and Mg powder (3.79 g, 156 mmol) was added portionwise at 60°C over 30 min. The mixture was stirred at 60°C for 10 mins. The mixture was poured into HCl (160 mL, 2 M) and extracted with PE / EtOAc (2 x 200 mL, 1:1). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , filtered, concentrated in vacuo and purified twice by silica gel column (100-200 mesh, PE:EtOAc=50:1 to 10:1) to give a crude product, which 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.

[0529] 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, 30-90 AB, MS ESI C 28 H 44 F3O[M+H-H2O] + The calculated value is 453, and the measured value is 453.

[0530] Example 4. Synthesis of Compounds 1-A and 1-B.

[0531]

[0532] Step 1. Benzoyl chloride (59.7 mg, 0.425 mmol) was added to a solution of compound 1 (100 mg, 0.212 mmol) in pyridine (3 mL) 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 (2x10 mL). The combined organic layer was dried with Na2SO4, filtered and concentrated in vacuo to obtain a crude product. The crude product was purified by silica gel column (PE / EtOAc=10 / 1) to obtain the desired product A-9 (150 mg, crude material), which was a solid.

[0533] LCMS Rt = 1.544 min, 2 min chromatography, 30-90 AB, MS ESI C 35 H 49 The calculated value of F3O3[M+Na]+ is 597, and the found value is 597.

[0534] Step 2. A-9 (580 mg, 1.00 mmol) was separated and purified by SFC (column: AD (250 mm*30 mm, 5 μm), gradient: 45% B (A = NH 3 H 2 O, B = MeOH), flow rate: 60 mL / min) to obtain A-10-A (200 mg, 34%, 95.5% deuterated) by SFC (column: Chiralpak AD-3100×4.6 mm ID, 3 μm, mobile phase: A: CO 2 B: isopropanol (0.05% DEA).

[0535] Gradient: 5% to 40% B in 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.)), which was a solid, and A-10-B (215 mg, 37%, 99.5% deionized water were analyzed by SFC (column: Chiralpak AD-3 100×4.6 mm ID, 3 μm, mobile phase: A: CO2 B: isopropanol (0.05% DEA).

[0536] Gradient: 5% to 40% B in 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.)) which was a solid.

[0537] A-10-A: 1H NMR (400MHz, CDCl3) δ8.07-8.02(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).

[0538] A-10-B: 1 H NMR (400MHz, CDCl3) δ8.07-8.02 (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).

[0539] 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 H O (2 mL) at 25 ° C. The solution was stirred at 50 ° C for 48 hours. The reaction solution was extracted with EtOAc (2x10 mL). The combined organic layers were dried over Na SO , filtered and concentrated in vacuo to give a crude product, which was triturated with MeCN (2x5 mL) to give the desired product, compound 1-A (148 mg, 84%), as a solid.

[0540] Compound 1-A: 1 H NMR (400 MHz, 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, 30-90 AB, MS ESI C28 H 44 Calculated value of F3O[M+H-H2O]+ 453, found 453.

[0541] 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 H O (2 mL) at 25 ° C. The solution was stirred at 50 ° C for 48 hours. The reaction solution was extracted with EtOAc (2x10 mL). The combined organic layers were dried over Na SO , filtered and concentrated in vacuo to give a crude product, which was triturated with MeCN (2x5 mL) to give the desired product, compound I-B (139 mg, 85%), as a solid.

[0542] Compound 1-B: 1 H NMR (400MHz, CDCl3) δ5.38-5.36 (m, 1H), 3.33-3.31 (m, 1H), 2.49-2.48 (m, 2H), 2.12-1.92 (m, 5 H), 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)

[0543] LCMS Rt = 1.500 min, 2 min chromatography, 30-90 AB, MS ESI C 28 H 44 F3O[M+H-H2O] + The calculated value is 453, and the measured value is 453.

[0544] Synthesis of Compound 1-A - Absolute Stereochemistry

[0545]

[0546] The experimental steps of intermediate ST-200-CF3_4A or A-7 can be found in Example 3.

[0547] Synthetic ST-200-096-004_1

[0548]

[0549] 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 N . The reaction mixture was quenched dropwise with HCl (50 mL) until the solution became clear. The reaction solution was extracted with EtOAc (3x30 mL). The combined organic layer was washed with saturated NaHCO 3 (50 mL), brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by flash column purification (0-12% EtOAc in PE) to obtain ST-200-096-004_2 (150 mg, 43%), which was a solid.

[0550] 1 H NMR (400MHz, CDCl3) δ5.40-5.34(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).

[0551] Synthetic ST-200-096-004_3

[0552]

[0553] To a solution of ST-200-096-004_2 (150 mg, 0.318 mmol) in pyridine (3 mL) was added BzCl (134 mg, 0.954 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 (2x40 mL). The organic layer was washed with brine (5x50 mL), dried over Na2SO4, filtered and concentrated. The crude material was purified by silica gel column (PE / EtOAc=10 / 1 to 4 / 1) to obtain ST-200-096-004_3 (120 mg, 66%) as a solid.

[0554] 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% NH3H2O ​​IPA)) to give ST-200-096-004_4 (100 mg, 84%) as a solid.

[0555] 1HNMR (400MHz, CDCl3) δ8.05 (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).

[0556] SFC Rt = 3.473 min, 10 min chromatography, AD_IPA(DEA)_5_40_2, 8ML_8MIN, 100% de.

[0557] Synthesis of compound 1-A

[0558]

[0559] 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 hours. The mixture was poured into water (20 mL) and extracted with EtOAc (2x40 mL). The combined organic layer was washed with brine (30 mL), dried over Na SO , filtered and concentrated. The residue was purified by flash column (PE / EtOAc=5 / 1 to 3 / 1) to obtain compound 1-A (48 mg, 59%), which was a solid.

[0560] 1 HNMR (400MHz, CDCl3) δ5.40-5.35(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).

[0561] LCMS Rt = 1.265 min, 2.0 min chromatography, 30-90AB, 100% purity, MS ESI C 28 H 44 The calculated value of F3O [M-H2O+H] = 453, the measured value is 453.

[0562] Example 5. Synthesis of Compounds 2, 2-A, and 2-B.

[0563]

[0564] 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 at 25° C. under H (25 psi) for 72 hours. The mixture was filtered. The filtrate was concentrated in vacuo to give B-1 (47 g, 94%) as a solid.

[0565] 1 H NMR (400MHz, CDCl3) δ3.69-3.51 (m, 1H), 2.51 (t, J=8.8Hz, 1H), 2.21-2.12 (m, 1H), 2.11 (s, 3H), 2.05-1.98 (m, 1H), 1.8 8-1.77 (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).

[0566] Step 2. To a suspension of MePPh3Br (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 obtain a crude product, which was ground from MeOH / water (1000 mL, 1: 1) at 50 ° C. After cooling, the mixture was filtered and the solid was washed with MeOH / water (2x500 mL, 1: 1) and dried in vacuo to obtain B-2 (45 g, 97%), which was a solid.

[0567] 1 H NMR (400MHz, CDCl3) δ4.84 (s, 1H), 4.70 (s, 1H), 3.69-3.51 (m, 1H), 2.08-1.98 (m, 1H), 1.88-1.6 2 (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).

[0568] 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 hours. PE (500 mL) was added to the mixture. 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 obtain B-3 (44 g, 98%), which was a solid.

[0569] 1 H NMR (400MHz, CDCl3) δ4.85 (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).

[0570] 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). TMSCF (18.0 g, 127 mmol) was added dropwise to the mixture at 10 ° C. The mixture was stirred at 10 ° C for 2 hours. TBAF (127 mL, 1M in THF, 127 mmol) was added to the mixture at 10 ° C. The mixture was stirred at 20 ° C for 3 hours. Water (200 mL) was added to the mixture. The mixture was concentrated in vacuo to remove THF. EtOAc (300 mL) was added to the residue. The organic layer was separated, washed with water (100 mL), brine (100 mL), dried over Na2SO4, filtered, concentrated in vacuo, ground from PE: DCM (500 mL, 20: 1), and recrystallized from MeCN (200 mL) to obtain B-4 (7.1 g) as a solid. The triturated and recrystallized filtrates 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, total yield 60%) as a solid.

[0571] 1 H NMR (400MHz, CDCl3) δ4.84 (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).

[0572] 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 H2O2 (38.1 mL, 10 M, aq.) were added dropwise to the mixture. The mixture was stirred at 50 ° C for 1 h. After cooling, Na2SO3 (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 ground from water (400 mL) to obtain B-5 (15 g, 98%) as a solid.

[0573] 1 H NMR (400MHz, CDCl3) δ3.68-3.58(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=6.4Hz, 3H), 1.00-0.88 (m, 2H), 0.85 (s, 3H), 0.75-0.68 (m, 1H), 0.67 (s, 3H).

[0574] Step 6. To a solution of B-5 (15 g, 17.7 mmol) in DCM (60 mL) and pyridine (42 mL) is added TsCl (14.1 g, 74.4 mmol). The mixture is stirred at 15 ° C for 2 hours. Water (2 mL) is added to the mixture and the mixture is stirred at 15 ° C for 16 hours. Water (100 mL) is added to the mixture. The mixture is extracted with PE / EtOAc (2: 1, 300 mL). The organic layer is separated, washed with HCl (200 mL, 1 M), water (100 mL), brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain B-6 (23 g, crude material), which is a solid.

[0575] 1H NMR (400MHz, CDCl3) δ7.78 (d, J=8.0Hz, 2H), 7.34 (d, J=8.0Hz, 2H), 3.96 (dd, J=3.2, 9.2Hz, 1H), 3.76 (dd, J=6.8, 9.2Hz, 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).

[0576] 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 h. To the mixture was added PhSO2Na (20.1 g, 123 mmol). The mixture was stirred at 50 ° C for 16 hours. DCM (200 mL), water (400 mL) and PE (2: 1, 400 mL) were added to the mixture under stirring. The organic layer was separated, washed with water (100 mL), brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo to 150 mL to form a solid. The mixture was filtered, washed with PE (100 mL), and dried in vacuo to obtain B-7 (12 g, 55%), which was a solid.

[0577] 1 H NMR (400MHz, CDCl3) δ7.95-7.88 (m, 2H), 7.70-7.61 (m, 1H), 7.60-7.51 (m, 2H), 3.13 (d, J=13.2Hz, 1H), 2.84 (dd, J=9.2 , 14.0Hz, 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).

[0578] Step 8. To a solution of i-Pr2NH (573 mg, 5.67 mmol) in THF (10 mL) was added BuLi (1.88 mL, 2.5 M in hexane, 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 hrs and at 50 ° C for 2 hours. 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 Na 2 SO 4 , 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.

[0579] 1 H NMR (400MHz, CDCl3) δ7.95-7.85 (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).

[0580] Step 9. To a solution of B-8 (0.5 g, 0.815 mmol) in MeOH (50 mL) was added NiBr2 (2 mg, 0.009 mmol). Magnesium powder (2.22 g, 91.4 mmol) was then added portionwise at 60 ° C over 30 min. The mixture was stirred at 60 ° C for 1 h. The mixture was poured into citric acid (200 mL, 10% aq.) and extracted with PE / EtOAc (2x200 mL, 1: 1). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na2SO4, 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.

[0581] 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, 30-90 AB, no MS signal. HRMS ESI C 28 H 46 F3O[M+H-H2O] + The calculated value is 455.3495, and the measured value is 455.3489.

[0582] Step 10. Compound 2 (264 mg) was separated twice by silica gel column (300-400 mesh, 30*250 mm, PE:EtOAc=30:1 to 15:1) to give compound 2-A (56 mg, 21%) and compound 2-B (101 mg, 38%), both as solids.

[0583] The diastereomeric ratio of 2-A and 2-B was assessed by conversion of the alcohol to the benzoate: 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 mins. PE (5 mL) was added to the mixture. The mixture was washed with NaHCO3 (2 mL, saturated aqueous solution), HCl (2 mL, 1 M, aq.), NaHCO3 (2 mL, saturated aqueous solution), and purified by prep-TLC (PE:DCM=1:1) to give 2-B-Bz for SFC analysis (98.7% de ("Column: Chiralpak AD-3150×4.6 mm I.D., 3 um Mobile phase: A: CO2 B: isopropanol (0.05% DEA) Gradient: 5% to 40% B in 5 minutes and maintained at 40% for 2.5 minutes, then 5% B maintained for 2.5 minutes, flow rate: 2.5 mL / min, column temperature: 35°C")).

[0584] 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 mins. To this mixture was added PE (5 mL). The mixture was washed with NaHCO3 (2 mL, saturated aqueous solution), HCl (2 mL, 1 M, aq.), NaHCO3 (2 mL, saturated aqueous solution), and purified by prep-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 um mobile phase: A: CO2 B: isopropanol (0.05% DEA) gradient: 5% to 40% B in 5 minutes and maintained at 40% for 2.5 minutes, then 5% B maintained for 2.5 minutes, flow rate: 2.5 mL / min, column temperature: 35°C)).

[0585] 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, 30-90 AB, MS ESI C 28 H 46 F3O[M+H-H2O] + The calculated value is 455, and the measured value is 455.

[0586] 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, 30-90 AB, MS ESI C 28 H 46 F3O[M+H-H2O]+ The calculated value is 455, and the measured value is 455.

[0587] Synthesis of compound 2-A - absolute stereochemistry

[0588]

[0589] The experimental steps of intermediate ST-200-CF3_6C can be found in Example 5.

[0590] Synthetic ST-200-096-001_1

[0591]

[0592] To THF (1mL) add n-BuLi (0.948mL, 2.5M in hexane, 2.37mmol), then add ST-200-CF3-6C (500mg, 0.949mmol) solution in THF (4mL) at -70 ℃.After stirring 30mins at -70 ℃, add (2R)-2-(propyl-2-yl) oxirane (122mg, 1.42mmol) at -70 ℃.Mixture is gradually warmed to 25 ℃ and stirred 16 hours at 25 ℃.Mixture is quenched with saturated NH4Cl (15mL) and extracted with EtOAc (3x10mL).Separate organic layer, use Na2SO4 dry, filter and concentrate to obtain ST-200-096-001_1 (560mg, thick material), it is oily matter, and it is directly used in next step.

[0593] Synthetic ST-200-096-001_2

[0594]

[0595] 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 N . The reaction mixture was quenched dropwise with HCl (60 mL) until the solution became clear. The reaction solution was extracted with EtOAc (3x30 mL). The combined organic layer was washed with saturated NaHCO 3 (50 mL), brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by flash column purification (0-12% EtOAc in PE) to obtain ST-200-096-001_2 (150 mg, 46%), which was a solid.

[0596] 1H NMR (400MHz, CDCl3) δ3.35-3.26 (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).

[0597] Synthetic ST-200-096-001_3

[0598]

[0599] 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 (2x40 mL). The organic layer was washed with brine (5x50 mL), dried over Na2SO4, filtered and concentrated. The crude material was purified by silica gel column (PE / EtOAc=10 / 1 to 4 / 1) to obtain ST-200-096-001_3 (150 mg, 62%) as an oil.

[0600] 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% NH3H2O ​​IPA)) to give ST-200-096-001_3 (120 mg, 81%) as a solid.

[0601] 1 HNMR (400MHz, CDCl3) δ8.05 (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, 4 H), 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).

[0602] SFC Rt = 4.117 min, 10 min chromatography, AD_3_IPA_EtOH_5_40_25ML, 99% de.

[0603] Synthesis of compound 2-A

[0604]

[0605] 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 hrs, poured into water (20 mL) and extracted with EtOAc (2x40 mL). The combined organic layer was washed with salt water (30 mL), dried over Na SO , filtered and concentrated. The residue was purified by flash column (PE / EtOAc=5 / 1 to 3 / 1) to obtain compound 2-A (82 mg, 83%), which was a solid.

[0606] 1 HNMR (400MHz, CDCl3) δ3.34-3.28 (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).

[0607] MS MS ESI C 28 H 47 F3O2Na[M+Na + ] calculated value = 495, measured value 495.

[0608] Example 6. Synthesis of Compound 3.

[0609]

[0610] Step 1. at -65 DEG C under N2 to n-BuLi (568 μ L, 2.5M in hexane, 1.42mmol) in THF (0.5mL) in a solution of B-7 (300mg, 0.5695mmol) in THF (2.5mL) is added dropwise. The mixture is stirred at -65 DEG C for 30 minutes. 2- (tert-butyl) oxirane (68.4mg, 0.6834mmol) is added dropwise at -65 DEG C. The mixture is stirred for another 30 minutes, then gradually warmed to 25 DEG C and stirred at 25 DEG C for 16 hours. The reaction mixture passes through saturated NH4Cl aqueous solution (30mL) cancellation, is extracted with ethyl acetate (3x20mL). The organic phase merged is washed with salt water (30mL), uses Na2SO4 drying, filters and is concentrated in vacuo to obtain C-1 (380mg, thick material), which is solid, which is directly used in the next step.

[0611] Step 2. Under N2, under stirring at 50 ℃, to a solution of C-1 (380 mg, 0.6062 mmol) and NiCl2 (7.81 mg, 0.06062 mmol) in anhydrous methanol (20 mL), Mg powder (580 mg, 24.2 mmol) was added in 4 portions. The reaction mixture was stirred at 60 ℃ for 1 hour. The reaction mixture was cooled and poured into ethyl acetate (150 mL). The mixture was washed with 1M HCl (3x200 mL), saturated NaHCO3 aqueous solution (200 mL), brine (200 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain a solid, which was purified by silica gel chromatography (PE: EtOAc = 8: 1) to obtain impure compound 3 (310 mg), which was a solid. It was purified by grinding in PE / DCM (15 mL / 1 mL) to obtain compound 3 (46 mg, 15%), which was a solid.

[0612] 1 H NMR (400MHz, CDCl3) δ3.16-3.05 (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).

[0613] 19 F NMR (400 MHz, CDCl3) δ 78.66.

[0614] LCMS Rt = 1.354 min, 2 min chromatography, 30-90 AB, MS ESI C29 H 48 F3O[M-H2O+H] + The calculated value is 469, and the measured value is 469.

[0615] Example 7. Synthesis of Compound 4.

[0616]

[0617] 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 h, (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropyl 4-methylbenzenesulfonate was added at -70 ° C, referring to Example 30 (169 mg, 0.57 mmol). The mixture was warmed to 25 ° C and stirred at this temperature for 16 hours. The mixture was quenched with saturated NH4Cl aqueous solution (5 mL). The mixture was extracted with EtOAc (2×8 mL), washed with brine (2×20 mL), dried over Na 2 SO 4 , filtered, and concentrated in vacuo to give the crude product D-1 (300 mg, crude) as an oil, which was used directly in the next step.

[0618] Step 2. Mg powder (549 mg, 22.9 mmol) and NiCl (5 mg) were added to a solution of D-1 (300 mg, thick material) in MeOH (15 mL) at 60 ° C. The mixture was stirred for 1 h at 60 ° C. EtOAc (20 mL) and HCl aqueous solution (30 mL) were added. The mixture was extracted with EtOAc (2x30 mL). The combined organic layer was washed with water (3x50 mL), saturated NaHCO (2x50 mL), and salt solution (2x50 mL) to obtain a crude product, which was purified by flash column purification (0-30% EtOAc in PE) to obtain compound 4 (100 mg, impure), which was ground with CH at 25 ° C. CN (5 mL) was used to obtain compound 4 (50 mg, 50%), which was a solid.

[0619] 1 H NMR (400MHz, CDCl3) δ2.10-1.90 (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).

[0620] LCMS Rt = 1.264 min, 2 min chromatography, 30-90 AB, MS ESI C 27 H 41 F6O[M+H-H2O] + The calculated value is 495, and the measured value is 495.

[0621] Example 8. Synthesis of Compound E-1.

[0622]

[0623] 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 for 30 mins at 20° C. and for 1 h at 0° C. 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.

[0624] 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 mins. The solution was concentrated in vacuo to obtain a solid. The resulting catalyst residue was dissolved in pure 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 separated by distillation from the reaction mixture.

[0625] 1 H NMR (400MHz, DMSO-d6) 3.96 (s, 1H), 3.11-2.98 (m, 2H).

[0626] The ee of E-1 was determined by 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 hours. A solid precipitated, which was ground from petroleum ether to give the product (260 mg, 67%) as a solid. The ee of the product was determined to be 100% by chiral HPLC (column: CD-PH 250*4.6 mm ID, 5 um; mobile phase: 10% to 80% B in A (A: water with 0.069% TFAB: acetonitrile); flow rate: 0.8 mL / min; column temperature: 30 ° C).

[0627] Example 9. Synthesis of Compound 5.

[0628]

[0629] Step 1. at -65 ℃ under N2 to n-BuLi (0.704mL, 2.5M in hexane, 1.76mmol) in THF (0.5mL) in the solution of B-7 (310mg, 0.588mmol) in THF (2.5mL) is added dropwise and the reaction is stirred at -65 ℃ for 30 minutes.-65 ℃ of E-1 (78.9mg, 0.705mmol) solution is added dropwise. The mixture is stirred for 30 minutes, then gradually warmed to 25 ℃ and stirred at 25 ℃ for 16 hours. The reaction mixture passes through saturated NH4Cl aqueous solution (30mL) is quenched, extracted with ethyl acetate (3x20mL). The organic phase merged is washed with salt water (30mL), uses Na2SO4 drying, filters and is concentrated in vacuo to obtain E-2 (300mg, thick material), which is solid, which is directly used in the next step.

[0630] Step 2. Under N2, magnesium powder (454 mg, 18.7 mmol) was added to a solution of E-2 (300 mg, 0.469 mmol) and nickel (II) chloride (15.1 mg, 0.117 mmol) in anhydrous methanol (20 mL) at 50 ° C under stirring to initiate continuous hydrogen generation. The reaction mixture was stirred at 60 ° C for 1 hour. The reaction mixture was quenched dropwise by 2M HCl (100 mL) at 10 ° C until the solid dissolved. After extraction with EtOAc (2x150 mL), the combined organic layer was washed with saturated NaHCO3 aq. (300 mL), brine (300 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain a solid, which was purified by silica gel chromatography (PE: THF = 12: 1) to obtain the product. The residue was recrystallized from MeCN (10 mL) to obtain compound 5 (41 mg, 18%), which was a solid.

[0631] 1 H NMR (400MHz, CDCl3) δ3.75-3.65 (m, 1H), 2.10-1.95 (m, 3H), 1.90-1.75 (m, 2H), 1.73-1.66 (m, 5 H), 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).

[0632] LCMS Rt = 1.226 min, 2.0 min chromatography, 30-90AB.

[0633] Example 10. Synthesis of Compound 6.

[0634]

[0635] Step 1. at -65 ℃ under N2 to n-BuLi (0.568mL, 2.5M in hexane, 1.42mmol) in THF (0.5mL) in the solution of B-7 (250mg, 0.474mmol) in THF (2.5mL) is added dropwise.After stirring at -65 ℃ for 30 minutes, at -65 ℃, a solution of (2S)-2-methyloxirane (32.9mg, 0.568mmol) is added dropwise. The mixture is stirred for another 30 minutes, then gradually warmed to 25 ℃ and stirred at 25 ℃ for 16 hours. The reaction mixture is saturated with NH4Cl aqueous solution (30mL) is quenched, and extracted with ethyl acetate (3x20mL). The organic phase merged is washed with salt water (30mL), uses Na2SO4 drying, filters and is concentrated in vacuo to obtain F-1 (250mg, thick material), which is solid, which is directly used in the next step.

[0636] Step 2. Under N2, magnesium powder (413 mg, 17.0 mmol) was added to a solution of F-1 (250 mg, 0.427 mmol) and nickel (II) chloride (13.7 mg, 0.106 mmol) in anhydrous methanol (20 mL) at 50 ° C with stirring to initiate continuous hydrogen generation. The reaction mixture was stirred at 60 ° C for 1 hour. The reaction mixture was quenched by 2M HCl (100 mL) added dropwise at 10 ° C until the solid dissolved. After extraction with EtOAc (2x150 mL), the combined organic layers were washed with saturated NaHCO3 aq. (300 mL), brine (300 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain a solid, which was purified by silica gel chromatography (PE / THF=12 / 1) to obtain impure compound 6 (100 mg, containing 12% 22,23-olefins as determined by NMR), which was a solid. Under N2, Pd / C (26.5 mg, 0.224 mmol) was added to a solution of impure compound 6 (100 mg, 0.224 mmol) in EtOAc (10 mL) to remove unwanted olefins. The mixture was degassed in vacuo and purged several times with H2. The mixture was stirred for 2 hours at 25 ° C under H2. The mixture was filtered and the filtrate was concentrated in vacuo to obtain residue. The residue was purified by recrystallization from MeCN (10 mL) to obtain compound 6 (35 mg, 19%), which was a solid.

[0637] 1H NMR (400MHz, CDCl3) δ3.75-3.65 (m, 1H), 2.10-1.95 (m, 3H), 1.90-1.75 (m, 2H), 1.73-1.66 (m, 4 H), 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).

[0638] LCMS Rt = 1.222 min, 2.0 min chromatography, 30-90 AB, MS ESI C 28 H 42 F3O[M+H-H2O] - The calculated value is 427, and the measured value is 427.

[0639] Example 11. Synthesis of Compounds 7, 7-A, and 7-B.

[0640]

[0641]

[0642] X-ray data of compound 7 confirmed the stereochemistry of compound 7-A and compound 7-B.

[0643] Step 1. To a solution of compound G-1 (5.0 g, 12.8 mmol) in EtOAc (150 mL) was added Pd / C (1.0 g), and the mixture was stirred at 50 ° C under hydrogen (50 psi) overnight. The mixture was filtered through a pad of celite and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 15: 1) to give pure product G-2 (3.7 g, 74%).

[0644] 1 H NMR: (400MHz, CDCl3) δ3.66 (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).

[0645] Step 2. DMP (19.5 g, 46 mmol) was added to a solution of G-2 (10 g, 25.6 mmol) in DCM (200 mL) at 25 ° C. The mixture was stirred at 25 ° C for 30 minutes. 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 Na SO (2x300 mL) and salt solution (2x300 mL), and dried over Na SO, filtered, and concentrated in vacuo to obtain a crude product G-3 (9 g), which was a solid that was used for the next step without further purification.

[0646] 1 H NMR (400MHz, CDCl3) δ3.66 (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).

[0647] Step 3. TMSCF3 (5.11 g, 36.0 mmol) was added dropwise to a mixture of G-3 (7 g, 18.0 mmol) and CsF (5.46 g, 36.0 mmol) in THF (70 mL) at 0 ° C. The mixture was stirred and kept below 10 ° C for 10 minutes. TBAF (45.0 mL, 1 M in THF, 45.0 mmol) was added at 10 ° C. The mixture was stirred and kept below 10 ° C for 10 minutes. The mixture was then treated with water (200 mL) and extracted with EtOAc (2x200 mL). The combined organic layer was washed with brine (500 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EtOAc=5 / 1) to obtain G-4 (5.55 g, 67%), 4H), 0.84 (s, 3H), 0.73-0.63 (m, 4H).

[0648] Step 4. under N2 at 0 DEG C to LiAlH4(1.03g, 27.4mmol) in THF (80mL) suspension was added dropwise a solution of G-4 (6.3g, 13.7mmol) in THF (20mL). The reaction was stirred at 25 DEG C for 2h. The reaction was quenched with water / THF (1 / 10, 40mL), then 2M HCl (100mL) was added at 0 DEG C. The mixture was extracted with EtOAc (2x100mL). The combined organic phase was washed with salt water (300mL), used Na2SO4 dried, filtered and concentrated to obtain G-5 (5g, crude material), which was a solid.

[0649] 1 H NMR (400MHz, CDCl3) δ3.61 (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).

[0650] Step 5. DMP (5.89 g, 13.9 mmol) was added to a solution of G-5 (3 g, 6.96 mmol) in DCM (30 mL) at 20 ° C. The reaction mixture was stirred at 20 ° C for 20 minutes and quenched with saturated NaHCO aqueous solution (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 Na SO aqueous solution (3x50 mL), brine (50 mL), dried over Na SO, filtered and concentrated in vacuo, and the residue was ground from CH CN (5 mL) at 20 ° C to obtain G-6 (1.3 g, 44%), which was a solid.

[0651] 1 H NMR (400MHz, CDCl3) δ9.78-9.75 (t, J=2.00Hz, 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).

[0652] Step 6. At 60 ° C, a solution of bromocyclobutane (5 g, 37.0 mmol) in THF (8 mL) was added dropwise to a suspension of Mg (2 g, 82.2 mmol) and I (10 mg) in THF (2 mL). The mixture was stirred at 60 ° C for 1 h. The mixture was diluted with THF (10 mL) and used directly. 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 (3x20 mL). The organic layer was separated and concentrated in vacuo, purified by silica gel (PE / EtOAc=20 / 1 to 5 / 1) to obtain a crude product, which was recrystallized from MeCN / H2O (5 / 2, 15 mL) to obtain compound 7 (250 mg, 37%), which was a solid.

[0653] 1H NMR (400MHz, CDCl3) δ3.49-3.38 (m, 1H), 2.40-2.25 (m, 1H), 2.10-1.90 (m, 5H), 1.90-1.60 (m, 9 H), 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).

[0654] HPLC Rt = 6.10 min, 8.0 min chromatography, 50-100AB.

[0655] MS ESI C 29 H 46 F3O[M+H-H2O] + The calculated value is 467, and the measured value is 467.

[0656] 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 H2O (5 mL) and washed with HCl (10 mL, 1M, aq.), NaHCO3 (10 mL, saturated aqueous solution), dried over Na2SO4, filtered, and concentrated in vacuo to give a 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 um; 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% deionized water ("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 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% deionized water ("Column: Chiralpak AD-3 150×4.6 mm I.D., 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")).

[0657] 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.H2O (399 mg, 9.52 mmol) in water (1 mL). The mixture was stirred at 60 ° C for 24 h. After vacuum removal of the organic solvent, the mixture was treated with H2O (5 mL) and extracted with EtOAc (3x5 mL). The organic layer was washed with brine (2x15 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was ground from CH3CN (2 mL) at 25 ° C to obtain compound 7-A (43 mg, 70%), which was a solid.

[0658] 1 H NMR (400MHz, CDCl3) δ3.49-3.41 (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).

[0659] HPLC Rt = 6.78 min, 8.0 min chromatography, 30-90AB.

[0660] MS ESI C 29 H 46 F3O[M+H-H2O] + The calculated value is 467, and the measured value is 467.

[0661] 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.H2O (406 mg, 9.68 mmol) in water (1 mL). The mixture was stirred at 60 ° C for 24 h. After vacuum removal of the organic solvent, the mixture was treated with H2O (5 mL) and extracted with EtOAc (3x5 mL). The organic layer was washed with brine (2x15 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was ground from CH3CN (2 mL) at 25 ° C to obtain compound 7-B (52 mg, 72%), which was a solid.

[0662] 1H NMR (400MHz, CDCl3) δ3.48-3.37 (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).

[0663] HPLC Rt = 6.78 min, 8.0 min chromatography, 30-90AB

[0664] MS ESI C 29 H 46 F3O[M+H-H2O] + The calculated value is 467.3495, and the measured value is 467.3.

[0665] Example 12. Synthesis of Compound H-1

[0666]

[0667] 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 mins. A solution of H-0 (2 g, 14.9 mmol) in THF (5 mL) was added dropwise at 15 ° C. The mixture was stirred for 16 hours at 15 ° C. The mixture was quenched with Sat.NH4Cl (50 mL) and extracted with EtOAc (3x20 mL). The combined organic phases were dried with Na2SO4, filtered, and concentrated to obtain H-1 (1.8 g, 82%) as a solid.

[0668] 1 H NMR (400MHz, CDCl3) δ2.72 (s, 2H), 2.20-1.85 (m, 8H).

[0669] Example 13. Synthesis of Compound 8.

[0670]

[0671] Step 1. Add a solution of B-7 (2 g, 3.79 mmol) in THF (15 mL) to a solution of THF (5 mL) and BuLi (3.78 mL, 2.5 M in hexane, 9.47 mmol) at -70 ° C. After stirring for 1 h at -70 ° C, add a solution of H-1 (1.68 g, 5.68 mmol) in THF (5 mL) at -70 ° C. The mixture is stirred for another 1 h at -70 ° C. The mixture is warmed to 25 ° C and stirred for 16 hrs and quenched by adding NH4Cl (50 mL, saturated aqueous solution). The mixture is extracted with EtOAc (2x30 mL). The organic layer is separated, dried with Na2SO4, filtered, concentrated, and purified by combi-flash (0-10% EtOAc in PE) to obtain H-2 (250 mg, 10%), which is a solid, and 1.8 g starting material, which is recovered.

[0672] 1 H NMR (400MHz, CDCl3) δ8.00-7.92(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).

[0673] Step 2. Mg powder (355 mg, 14.8 mmol) was added to a solution of H-2 (250 mg, 0.37 mmol) in MeOH (15 mL) at 55 ° C. The mixture was stirred at 60 ° C for 16 hours. The mixture was quenched with HCl (50 mL, 1 N) until the reaction became clear and extracted with DCM (2x30 mL). The combined organic phases were dried with Na SO , filtered, concentrated, and purified by flash column (0-10% EtOAc in PE) to obtain compound 8 (55 mg, 28%), which was a solid.

[0674] 1 H NMR (400MHz, CDCl3) δ2.20-1.73(m, 9H), 1.73-1.58(m, 7H), 1.58-0.85(m, 1 1H), 0.85-1.00(m, 8H), 1.00-0.86(m, 5H), 0.85(s, 3H), 0.72-0.62(m, 4H).

[0675] LCMS Rt = 1.286 min, 2 min chromatography, 30-90 AB, MS ESI C 30 H 46 F5O[M-H2O+H] + The calculated value is 517, and the measured value is 517.

[0676] Example 14. Synthesis of Compound 9.

[0677]

[0678] To a suspension of Mg (1.37 g, 56.5 mmol) and I (10 mg) in THF (2 mL) was added 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. 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 (3x20 mL). The organic layer was separated, concentrated in vacuo, purified by silica gel column (PE / EtOAc=20 / 1 to 5 / 1) to obtain a crude product, which was recrystallized from CH3CN (10 mL) to obtain compound 9 (180 mg, 27%), which was a solid.

[0679] 1 H NMR (400MHz, CDCl3) δ4.05-3.97 (m, 2H), 3.41-3.25 (m, 3H), 2.10-1.91 (m, 3H), 1.88-1.57 (m, 7 H), 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).

[0680] HPLC Rt = 4.73 min, 8.0 min chromatography, 50-100AB.

[0681] MS ESI C 30 H 48 F3O2[M+H-H2O] + The calculated value is 497, and the measured value is 497.

[0682] Example 15. Synthesis of Compound J-1.

[0683]

[0684] To a mixture of trimethylsulfuronium iodide (30.6 g, 150 mmol) in THF (100 mL) was added NaH (5.98 g, 60% in mineral oil, 150 mmol) in portions at 0°C under N2. The mixture was stirred at 0°C for 30 mins. 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 hours. The mixture was poured into ice-water (500 mL) in portions and extracted with DCM (2x500 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 Combi-flash (EtOAc in PE, 0% to 40%) to obtain J-1 (1.5 g, 13%) as an oil.

[0685] 1 H NMR (400MHz, CDCl3) δ4.11-3.90 (m, 3H), 3.66 (d, J=10.0Hz, 1H), 3.03 (d, J=4.4Hz, 1H), 2.94 (d, J=4.0Hz, 1H), 2.34-2.23 (m, 1H), 2.00-1.88 (m, 1H).

[0686] Example 16. Synthesis of Compound 10.

[0687]

[0688] Step 1. under N2 at-70 ℃ to n-BuLi (0.95mL, 2.38mmol, 2.5M) in THF (2mL) solution of A-7 (see Example 3) (500mg, 0.95mmol) in THF (5mL) is added dropwise to obtain a suspension. After stirring at-70 ℃ for 30 minutes, a solution of J-1 (238mg, 2.38mmol) in THF (3mL) is added. The reaction is then stirred at-70 ℃ for 10 minutes and at 20 ℃ for 16 hours. The reaction is quenched with sat.NH4Cl (20mL), extracted with EtOAc (3x20mL). The combined organic phase is washed with salt water (50mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product J-2 (500mg), which is a solid, which is directly used in the next step.

[0689] LCMS Rt = 0.925 min, 1.5 min chromatography, 5-95 AB, MS ESI C 34 H 47 F3O5SNa[M+Na] + The calculated value is 647, and the measured value is 647.

[0690] Step 2. under N2 under stirring at 55 ℃ to J-2 (300mg, 0.48mmol) in 20mL anhydrous methanol solution, add magnesium turnings (466mg, 19.2mmol) (activated with 0.5% HCl aqueous solution, water, anhydrous ethanol and MTBE) and NiCl2 (12.4mg, 0.96mmol) to initiate continuous hydrogen generation. After adding two more batches of 466mg magnesium turnings, most of the starting material is consumed. The reaction mixture is quenched by 2M HCl (100mL) added dropwise at 10 ℃ until the solid dissolves. After extraction with DCM (3x80mL), the combined organic phase is washed with brine (100mL), dried over Na2SO4, filtered and concentrated. The residue is purified by Combi-flash (0%~50% EtOAc in PE) to obtain compound 10 (46mg, 20%), which is a solid.

[0691] 1 H NMR (400MHz, CDCl3) δ5.43-5.32 (m, 1H), 4.08-3.98 (m, 1H), 3.95-3.85 (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).

[0692] LCMS Rt = 1.121 min, 2 min chromatography, 30-90 AB, MS ESI C 30 H 46 F3O3NNa[M+MeCN+Na] + The calculated value is 548, and the measured value is 548.

[0693] Example 17. Synthesis of Compound 11.

[0694]

[0695] Step 1. at -65 DEG C under N2 to n-BuLi (452 ​​μ L, 2.5M in hexane, 1.13mmol) in THF (0.5mL) in a solution of B-7 (200mg, 0.3797mmol) in THF (2.5mL) was added dropwise and stirred at -65 DEG C for 30 minutes.Then, diisopropylamine (114mg, 1.13mmol) was added dropwise at -65 DEG C, and 1,6-dioxaspiro [2.5] octane (65.0mg, 0.5695mmol) was then added dropwise at -65 DEG C. The mixture was stirred for another 30 minutes, then gradually warmed to 25 DEG C and stirred at 25 DEG C for 16 hours. The reaction mixture was quenched with saturated NH4Cl aqueous solution (30mL), extracted with ethyl acetate (3x20mL). The combined organic phases were washed with brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo to give K-1 (380 mg, crude) as a solid, which was used directly in the next step.

[0696] Step 2. Mg (0.520 g, 21.7 mmol) and NiCl (3.51 mg, 0.0271 mmol) were added to a solution of K-1 (0.348 g, 0.543 mmol) in MeOH (20 mL) at 60 ° C. The mixture was stirred at 60 ° C for 1 hour. The reaction mixture was cooled to 25 ° C. The mixture was added to HCl (20 mL, 1 M in water). The mixture was extracted with EtOAc (2x20 mL), washed with NaHCO (2x40 mL) and brine (2x40 mL), washed with Na SO dried, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column (PE / EtOAc=10 / 1 to 2 / 1) to obtain 66 mg of impure compound 11, which was a solid. It was ground from CH CN (5 mL) at 25 ° C to obtain compound 11 (30 mg, 11%), which was a solid.

[0697] 1 H NMR (400MHz, CDCl3) δ3.84-3.64(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).

[0698] LCMS Rt = 1.170 min, 2.0 min chromatography, 30-90 AB, MS ESI C 29 H 46 F3O2[M+H-H2O] + The calculated value is 483, and the measured value is 483.

[0699] Example 18: Synthesis of Compound 1839

[0700]

[0701] For the experimental steps of intermediate ST-200-INT_2 or A2, please refer to Example 3.

[0702] Synthesis of ST-200-CF3_1A

[0703]

[0704] 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. The mixture was stirred at 10 ° C for 16 hours. TLC showed that the 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 for 1 h at 10 ° C. TBAF (91.2 mL, 1 M in THF, 91.2 mmol) was added to the mixture. The mixture was stirred for another 1 h at 10 ° C. The mixture was concentrated in vacuo. The residue was dissolved in EtOAc (100 mL), washed with water (3x100 mL) and concentrated in vacuo to give a crude product, which was combined with another batch of 9.5 g ST-200-INT_2 and purified by silica gel column in four parts (PE: EtOAc = 30: 1 to 20: 1) to give ST-200-CF3_1B (2.3 g, purity 83%, yield 8%) and ST-200-CF3_1A (6.2 g, purity 32%, yield 8%). 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, purity 94%).

[0705] Note: ST-200-CF3_1A and ST-200-CF3_1B 3 JH, CF3 (FDCS) identification. (J.Org.Chem.2015, 80, 1754)

[0706] ST-200-CF3_1A:

[0707] 1H NMR (400MHz, CDCl3) δ5.43-5.33 (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).

[0708] ST-200-CF3_1B:

[0709] 1 H NMR (400MHz, CDCl3) δ5.54-5.41 (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).

[0710] Synthesis of ST-200-CF3_2A

[0711]

[0712] 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. Then, EtOH (4.5 mL), NaOH (15.6 mL, 5 M, aq.) and H2O2 (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, Na2SO3 (100 mL, 10%, aq.) was added to the mixture. The mixture was extracted with EtOAc (100 mL). The organic layer was separated and purified by silica gel column (PE: EtOAc = 10: 1 to 7: 1) to obtain ST-200-CF3_2A (1.2 g, purity 79%, yield 30%), which was a solid.

[0713] 1 H NMR (400MHz, CDCl3) δ5.42-5.32 (m, 1H), 3.64 (dd, J=2.8, 10.4Hz, 1H), 3.36 (dd, J=6.8, 10.4Hz, 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).

[0714] Synthesis of ST-200-CF3_3A

[0715]

[0716] 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 hours. 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 obtain ST-200-CF3_3A (1.05 g, 64%) as a solid.

[0717] 1 H NMR (400MHz, CDCl3) δ7.78 (d, J=8.4Hz, 2H), 7.34 (d, J=8.4Hz, 2H), 5.40-5.33 (m, 1H), 3.97 (dd, J=2.8, 9.2Hz, 1H), 3.77 ( dd, J=6.4, 9.2Hz, 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).

[0718] Synthesis of ST-200-CF3_4A

[0719]

[0720] 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 hours. 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 ground from PE / DCM (10 mL, 5:1) to obtain ST-200-CF3_4A (600 mg, 61%) as a solid.

[0721] 1H NMR (400MHz, CDCl3) δ7.98-7.87 (m, 2H), 7.70-7.52 (m, 3H), 5.39-5.31 (m, 1H), 3.14 (d, J=14.4Hz, 1H), 2.85 (dd, J=9.6 , 14.0Hz, 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).

[0722] Synthesis of E-322_6_1

[0723]

[0724] Under N2, diisopropylamine (3.76mmol, 380mg) was added to THF (2mL) at -70°C, followed by n-BuLi (3.42mmol, 1.36mL, 2.5M 3.0eq in hexane). The reaction was warmed to 15°C and then cooled to -70°C. A suspension of ST-200-CF3_4A (1.14mmol, 600mg) in THF (5mL) was added dropwise to obtain a suspension. After stirring at -70°C for 30 minutes, a solution of 2,2-dimethyloxirane (2.28mmol, 218mg, 2.0eq.) in THF (1mL) was added over 5 minutes (slightly exothermic, keeping internal T < -70°C). The reaction was then stirred at 15°C for 12 hours. The reaction was quenched with saturated NH4Cl (30mL) and extracted with EtOAc (3x10mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to give ST-200-CF 3 -5A (600 mg, crude) as a foam.

[0725] Synthesis 1839

[0726]

[0727] 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 under N2 for 2 hours. The mixture was quenched with HCl (100 mL, 2 M) until the reaction became clear and extracted with DCM (3x20 mL). The combined organic phases were washed with saturated NaHCO3 (50 mL), dried over Na2SO4, filtered, concentrated and purified by combi-flash (0-10% EtOAc in PE) to obtain 170 mg of impure product, which was then purified by prep-HPLC (column: DuraShell 150*25mm*5um), gradient: 7 B( ), flow rate: 30mL / min) to give 1839 (66 mg, 14%) as a solid.

[0728] 1 H NMR (400MHz, CDCl3) δ5.37-5.36 (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=6.8Hz, 3H), 0.68 (s, 3H).

[0729] LCMS Rt = 1.277 min, 2.0 min chromatography, 30-90AB, 100% purity, MS ESI C 27 H 42 F3O[M+H-H2O] + The calculated value is 439, and the measured value is 439.

[0730] Example 19: Synthesis of 1967

[0731]

[0732] The synthesis of ST-200-CF3_6C or B7 can be found in Example 5.

[0733] Synthesis 200-DA-C24_8_2

[0734]

[0735] At 0 ℃ under N 2, sodium hydride (18.0g, 60% in mineral oil, 452mmol) is added in batches to a mixture of trimethylsulfur oxide iodine (92.2g, 452mmol) in THF (300mL). The mixture is stirred at 0 ℃ for 30 minutes. A solution of dihydrofuran-3 (2H) -one (30g, 348mmol) in DMSO (300mL) is added dropwise at 0 ℃. The reaction mixture is stirred at 25 ℃ for 16 hours. The mixture is poured into ice-water (500mL) in batches and extracted with DCM (2x500mL). The combined organic phase is washed with brine (500mL), dried over Na 2 SO 4, filtered and concentrated at 30 ℃ to obtain 200-DA-C24_8_2 (32g, crude material), which is an oil. 3 g from the residue was purified by column (Al 2 O 3 , PE) to give 200-DA-C24_8_2 (0.6 g) as an oil.

[0736] 1 H NMR (400MHz, CDCl3) δ4.09-3.90 (m, 4H), 3.03 (d, J=4.4Hz, 1H), 2.93 (d, J=4.4Hz, 1H), 2.28 (td, J=8.0, 13.6Hz, 1H), 1.93 (m, 1H).

[0737] Synthetic ST-200-35-7_1

[0738]

[0739] At -65 ℃ under N 2, a suspension of ST-200-CF 3 -6C (500mg, 0.9493mmol) in THF (2.5mL) was added dropwise to a solution of n-BuLi (1.13mL, 2.5M in hexane, 2.84mmol) in THF (0.5mL). The mixture was stirred at -65 ℃ for 30 minutes. Diisopropylamine (286mg, 2.84mmol) was added at -65 ℃. Then, 200-DA-C24_8_2 (95.0mg, 0.9493mmol) was added dropwise at -65 ℃. The mixture was stirred for another 30 minutes, then gradually warmed to 25 ℃. The reaction mixture was stirred at 25 ℃ for 16 hours, quenched with saturated NH 4 Cl aqueous solution (30mL) and extracted with ethyl acetate (3x20mL). The combined organic phases were washed with brine (30 mL), dried over Na 2 SO 4 , 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.

[0740] Synthesis 1967

[0741]

[0742] Mg (686 mg, 28.6 mmol) is added to a solution of crude ST-200-35-7_1 (900 mg) in MeOH (10 mL). The reaction mixture is then stirred at 60 ° C for 2 h under N2. HCl aqueous solution (10 mL, 4 M) is added to the reaction mixture and then extracted with EtOAc (3x10 mL). The combined organic layer is washed with salt water (10 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain a crude product. The crude product is purified by silica gel chromatography (PE / EtOAc=30 / 1 to 10 / 1) to obtain impure 1967 (460 mg), which is a solid.

[0743] 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.

[0744] 1 H NMR (400MHz, CDCl3) δ4.10-4.00(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), 1.20-1.0 0 (m, 5H), 1.00-0.88 (m, 4H), 0.85 (s, 3H), 0.75-0.68 (m, 1H), 0.66 (s, 3H).

[0745] LCMS Rt = 1.148 min, 2.0 min chromatography, 30-90AB, 100% purity, MS ESIC 30 H 48 F3NO3Na[M+MeCN+Na] + The calculated value is 550 and the measured value is 550.

[0746] Example 20: Synthesis of 2080 and 2081

[0747]

[0748] The stereochemistry was confirmed by X-ray data.

[0749] The experimental steps of intermediate DA-35-6 can be found in Example 14.

[0750] Synthesis of DA-35-4_1A & DA-35-4_1B

[0751]

[0752] 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 the addition of H2O (5 mL). The mixture was washed with HCl (10 mL, 1M, aq.), NaHCO3 (10 mL, saturated aqueous solution), dried over Na2SO4, 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-350*4.6 mm I.D., 3 um; conditions: Base-IPA; gradient: 5-40% B; flow rate: 4 mL / min) to give DA-35-4_1A (56 mg, 36%, Rt = 4.889 minutes, 100% de) and DA-35-4_1B (80 mg, 51%, Rt = 5.283 minutes, 100% de).

[0753] DA-35-4_1A:

[0754] 1 H NMR (400MHz, CDCl3) δ8.04 (d, J=8.0Hz, 2H), 7.56 (t, J=8.0Hz, 1H), 7.45 (t, J=8.0Hz, 2H), 5.04-4.94 (m, 1H), 4.06-3.94 (m, 2H), 3.4 4-3.32 (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).

[0755] DA-35-4_1B:

[0756] 1H NMR (400MHz, CDCl3) δ8.04 (d, J=8.0Hz, 2H), 7.56 (t, J=8.0Hz, 1H), 7.45 (t, J=8.0Hz, 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).

[0757] Synthesized 2080

[0758]

[0759] A solution of LiOH.H2O (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 H2O (5 mL). The mixture was extracted with EtOAc (3x5 mL). The organic layer was washed with brine (2x15 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was ground from MeCN (2 mL) at 25 ° C to obtain 2080 (12 mg, 26%) as a solid.

[0760] 1 H NMR (400MHz, CDCl3) δ4.05-3.95 (m, 2H), 3.40-3.25 (m, 3H), 2.05-1.95 (m, 2H), 1.85-1.8 0 (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).

[0761] LCMS Rt = 1.205 min, 2.0 min chromatography, 30-90AB, 100% purity, MS ESI C 30 H 48 F3O2[M+H-H2O] - The calculated value is 497, and the measured value is 497.

[0762] Synthesis 2081

[0763]

[0764] A suspension of LiOH.H2O (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 H2O (5 mL). The mixture was extracted with EtOAc (3x5 mL). The organic layer was washed with brine (2x15 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was ground from MeCN (2 mL) at 25 ° C to obtain 2081 (32 mg, 48%), which was a solid.

[0765] 1 H NMR (400MHz, CDCl3) δ4.05-3.95 (m, 2H), 3.40-3.25 (m, 3H), 2.05-1.90 (m, 4H), 1.89-1.6 0 (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).

[0766] LCMS Rt = 1.205 min, 2.0 min chromatography, 30-90AB, 100% purity, MS ESI C 30 H 48 F3O2[M+H-H2O] - The calculated value is 497, and the measured value is 497.

[0767] Example 21: Synthesis of 2184

[0768]

[0769] The synthesis of ST-200-CF3_6C or B7 can be found in Example 5.

[0770] Synthesis of 200-TBU-E_2

[0771]

[0772] 200-TBU-E_1 (131 g, 998 mmol) is dissolved in 1690 mL 5N hydrochloric acid. The mixture is cooled to 0 ° C and a pre-cooled solution of sodium nitrite (109 g, 1.59 mol) in 400 mL water is added dropwise, and then the reaction mixture remains below 5 ° C. After 5 hours, the mixture is stirred at 25 ° C for 12 hours. Solid sodium carbonate (100 g) is carefully added in small portions. The reaction mixture is extracted with isopropyl ether (500 mL*2). The combined organic phase is washed with salt water (500 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue is separated by distillation to obtain 200-TBU-E_2 (48 g, 32%), which is a solid.

[0773] 1 H NMR (400MHz, CDCl3) δ4.12 (s, 1H), 1.13 (s, 9H).

[0774] Synthesis of 200-TBU-E_2

[0775]

[0776] 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 mins. 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 (2x500 mL), washed with brine (2x200 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give 200-TBU-E_3 (36 g, crude material) as a solid. The product was used in the next step without further purification.

[0777] 1 H NMR (400MHz, CDCl3) δ3.92-3.86 (m, 2H), 3.68-3.63 (m, 1H), 1.04 (s, 9H).

[0778] Synthesis of 200-TBU-E_4

[0779]

[0780] 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 20°C water bath. As the cyclization reaction proceeded, a potassium chloride precipitate formed. After 10 minutes, the bath temperature was slowly raised to 50°C. The product was separated by distillation to give 200-TBU-E_4 (6 g, 51.2%) as an oil. 100% ee was obtained after UV group protection.

[0781] 1 H NMR (400MHz, CDCl3) δ2.73-2.71 (m, 1H), 2.64-2.63 (m, 1H), 2.62-2.59 (m, 1H), 0.91 (s, 9H).

[0782] Method for EE examination of chiral epoxides

[0783]

[0784] n-BuLi (2.5M, 1.99mmol, 0.8mL) was added dropwise to a solution of (methylsulfonyl)benzene (342mg, 2.19mmol) in THF (5mL) at -70°C under N2. After stirring at -70°C for 30 minutes, a solution of 200-TBU-E_4 (100mg, 0.998mmol) was added. The reaction was then stirred at 25°C for 12 hours. The mixture was poured into ice-water (100mL) and extracted with EA (2X50mL). The combined organic layers were washed with brine (30mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EA=5 / 1) to give 200-TBU-E_4A (80mg, 31.3%) as an oil. The ee% of the product was determined to be 100% by chiral HPLC.

[0785] Synthesis DA-31-2_1

[0786]

[0787] Under N2, n-BuLi (0.416mL, 2.5M, 1.03mmol) is added to a solution of diisopropylamine (110mg, 1.09mmol) in THF (1mL) at -70°C. The resulting mixture is stirred at 0°C for 30 minutes. The mixture is recooled to -70°C. To this mixture is added a solution of ST-200-CF3-6C (250mg, 0.474mmol) in THF (2mL) at -70°C. The reaction mixture is stirred at -70°C for 1 hour. A solution of (R)-2-(tert-butyl)oxirane (56.8mg, 0.568mmol) in THF (1mL) is added at -70°C. The reaction mixture is slowly warmed to 15°C and stirred at 15°C for 16h. The reaction mixture is quenched with saturated NH4Cl aqueous solution (20mL) at 0°C. The mixture is extracted with EtOAc (2x20mL). The combined organic phases were washed with brine (10 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo to give crude DA-31-2_1 (300 mg) as a solid.

[0788] 1 H NMR (400MHz, CDCl3) δ7.95-7.85(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).

[0789] Synthetic DA-31-2

[0790]

[0791] 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 for 2 h under N2. Aqueous HCl (10 mL, 4 M) was added to the reaction mixture, which was then extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo to give a 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)2 / 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 2 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.

[0792] 1 H NMR (400MHz, CDCl3) δ3.20-3.05 (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).

[0793] LCMS Rt = 1.356 min, 2.0 min chromatography, 30-90AB, purity 99%, MS ESI calculated value C 29 H 48 F3O[M-H2O+H] + 469, measured value 469.

[0794] Example 22: Synthesis of 2285

[0795]

[0796] The synthesis of ST-200-CF3_6C or B7 can be found in Example 5.

[0797] Synthesis of ST-200-3CF3-A7R_1

[0798]

[0799] At -78 DEG C under N2, a suspension of ST-200-CF3_6C (250mg, 0.475mmol) in THF (2.5mL) was added dropwise to a solution of n-BuLi (568 μL, 2.5M in hexane, 1.42mmol) in THF (0.5mL). The mixture was stirred at -78 DEG C for 30 minutes. A solution of 2-(methyl)oxirane (41.3mg, 0.712mmol) was added dropwise at -78 DEG C. The mixture was stirred for another 30 minutes, then gradually warmed to 25 DEG C. The reaction mixture was stirred at 25 DEG C for 16 hours. The reaction mixture was quenched with saturated NH4Cl aqueous solution (30mL), extracted with EtOAc (3x20mL). The combined organic phases were washed with brine (30 mL), dried over Na 2 SO 4 , 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.

[0800] Synthesis 2285

[0801]

[0802] Under N2, Mg powder (556mg, 23.2mmol) is added to a solution of ST-200-3CF3-A7R_1 (340mg, 0.581mmol) in anhydrous methanol (30mL) at 60°C. The reaction mixture is quenched with 2M HCl (50mL) added dropwise at 10°C until the solid dissolves. After extraction with EtOAc (2x50mL), the organic layer is washed with saturated NaHCO3 (50mL), brine (50mL), dried over Na2SO4, filtered and concentrated. The residue is purified by flash column purification, eluted with PE / EtOAc=20 / 1 to 5 / 1, to obtain 2285 (80mg, impure, containing some 22-23 olefins), which is a solid that is used for the next step without further purification.

[0803] Synthetic ST-200-3CF3-A7R

[0804]

[0805] 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 at 50° C. under an H atmosphere (50 psi) for 16 h. The desired product was generated, the catalyst was removed by suction, 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

[0807] 1 H NMR (400MHz, CDCl3) δ3.74-3.72 (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)

[0808] LCMS Rt = 1.199 min, 2 min chromatography, 30-90 AB, purity 100%, MS ESI C 26 H 42 Calculated value of F3O[M+H-H2O]+: 427, found: 427.

[0809] Example 23: Synthesis of 2392

[0810]

[0811] The experimental steps of intermediate ST-200-CF3_4A or A7 can be found in Example 3.

[0812] Synthesis of ST-200-3CF3-C14_1

[0813] BuLi (0.476mL, 2.5M in hexane, 1.19mmol) is added to THF (0.5mL). A solution of ST-200-CF3_4A (250mg, 0.476mmol) in THF (3mL) is added at -70°C. The mixture is stirred at -70°C for 1h. 6,6-difluoro-1-oxaspiro [2.5] octane (210mg, 1.42mmol) is added at -70°C. The mixture is stirred for another 1h at -70°C. The mixture is warmed to 25°C and stirred for 16 hours. NH4Cl (50mL, saturated aqueous solution) is added to the mixture, and the mixture is then extracted with EtOAc (2x30mL). The organic layer is separated, dried with Na2SO4, filtered, and concentrated to obtain ST-200-3CF3-C14_1 (300mg, crude material), which is a solid, which is directly used in the next step.

[0814] Synthesis 2392

[0815]

[0816] 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 once at 55 ° C. The mixture was refluxed for 1 h at 65 ° C. The mixture was quenched with HCl (50 mL, 1 N) until the reaction became clear, then extracted with DCM (2x30 mL). The combined organic phases were dried with Na SO , filtered, concentrated, and purified by flash column (0-10% EtOAc in PE) to obtain impure product (110 mg), which was again purified by SFC (column: AD (250 mm * 30 mm, 5 μm), gradient: 35-35% B (A=0.1% NH / H O, B=MeOH), flow rate: 60 mL / min) to obtain 2392 (72 mg, 30%), which was a solid.

[0817] 1 H NMR (400MHz, CDCl3) δ5.38-5.35(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).

[0818] LCMS Rt = 1.248 min, 2.0 min chromatography, 30-90AB, 100% purity, MS ESI C30 H 44 F5O[M+H-H2O] + The calculated value is 515, and the measured value is 515.

[0819] Example 24: Synthesis of 2499

[0820]

[0821] The synthesis of DA-31-10_2 can be found in Example 11.

[0822] Synthesis 2499

[0823]

[0824] Under N2, at 0°C, a solution of DA-31-10_2 (6.3g, 13.7mmol) in THF (20mL) was added dropwise to a suspension of LiAlH4 (1.03g, 27.4mmol) in THF (80mL). The reaction was stirred at 25°C for 2h. The reaction was quenched with water / THF (1 / 10, 40mL). 2M HCl (100mL) was added to the mixture at 0°C and extracted with EtOAc (2x100mL). The combined organic phases were washed with brine (300mL), dried over Na2SO4, filtered and concentrated to obtain 2499 (5g, crude material), which was a solid. 100mg of impure DA-31-10_3 was ground with CH3CN (5mL) at 25°C for 3 hours to obtain 2499 (52mg, 52%), which was a solid.

[0825] 1 H NMR (400MHz, CDCl3) δ3.70-3.50(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).

[0826] LCMS Rt = 1.179 min, 2 min chromatography, 30-90 AB_E, purity 100%, MS ESI C 25 H 40 Calculated value of F3O[M+H-H2O]+: 413, found: 413.

[0827] Example 25: Synthesis of 2500

[0828]

[0829] The experimental steps of intermediate ST-200-CF3_4A can be found in Example 3.

[0830] Synthetic ST-200-31-6_1

[0831]

[0832] At -78 DEG C under N2, n-BuLi (568 μ L, 2.5M in hexane, 1.42mmol) is added to a solution of diisopropylamine (143mg, 1.42mmol) in THF (0.5mL). A suspension of ST-200-CF3_4A (250mg, 0.476mmol) in THF (2.5mL) is added dropwise. The mixture is stirred for 30 minutes at -78 DEG C. A solution of 2- (tert-butyl) oxirane (71.5mg, 0.715mmol) is added dropwise at -78 DEG C. The mixture is stirred for another 30 minutes, then gradually warmed to 25 DEG C. The reaction mixture is stirred at 25 DEG C for 16 hours. The reaction mixture is quenched with saturated NH4Cl aqueous solution (30mL), extracted with EtOAc (3x20mL). The combined organic phases were washed with brine (30 mL), dried over Na 2 SO 4 , 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.

[0833] Synthesis 2500

[0834]

[0835] 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 (2x50 mL). The combined organic phases were dried with Na SO , filtered, concentrated, and purified by flash column purification (0-10% EtOAc in PE) to obtain 112 mg of impure product, which was a solid. This product was ground with MeCN (3 mL) at 25 ° C to obtain 70 mg, which was a solid. The 70 mg product was dissolved in THF (8 mL) and treated with Lindlar (100 mg) under N . The mixture was vacuum degassed and purged (15 psi) several times with H . The mixture was stirred for 2 hrs at 25 ° C under H (15 psi). The mixture was filtered and the filtrate 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

[0836] 1 H NMR (CDCl3, 400MHz) δ5.40-5.30 (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).

[0837] LCMS Rt = 1.404 min, 2 min chromatography, 30-90AB, purity 100%, MS ESI C 28 H 46 F3O[M-H2O+H] + The calculated value is 467, and the measured value is 467.

[0838] Example 26: Synthesis of 2602

[0839]

[0840] The experimental steps of intermediate ST-200-CF3_4A or A7 can be found in Example 3.

[0841] Synthesis of ST-200-3CF3_C7S_1

[0842]

[0843] At -65 ℃ under N2, the suspension of ST-200-CF3-4A (250mg, 0.476mmol) in THF (2.5mL) is added dropwise to a solution of n-BuLi (0.568mL, 2.5M in hexane, 1.42mmol) in THF (0.5mL). Diisopropylamine (143mg, 1.42mmol) is added to the mixture at -65 ℃ and stirred for 30 minutes. A solution of (S)-2-methyloxirane (33.1mg, 0.571mmol) is added dropwise at -65 ℃. The mixture is stirred for another 30 minutes, then gradually warmed to 25 ℃. Reactant mixture is stirred at 25 ℃ for 16 hours. Reactant mixture passes through saturated NH4Cl aqueous solution (30mL) is quenched and extracted with ethyl acetate (3x20mL). The combined organic phases were washed with brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo to give ST-200-3CF 3 -C 7 S — 1 (250 mg, crude) as a solid which was used directly in the next step.

[0844] Synthesis 2602

[0845]

[0846] Under N2, Mg powder (415mg, 17.1mmol) is added to a solution of ST-200-3CF3-C7S_1 (250mg, 0.428mmol) and nickel chloride (II) (13.8mg, 0.107mmol) in anhydrous methanol (20mL) and the mixture is stirred at 50°C to initiate continuous hydrogen generation. The reaction mixture is stirred at 60°C for 1 hour. Then, the reaction mixture is quenched by 2M HCl (100mL) added dropwise at 10°C until the solid dissolves. After extraction with EtOAc (2x150mL), the combined organic layers are washed with saturated NaHCO3aq. (300mL), brine (300mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain a solid, which is purified by silica gel chromatography (PE:EtOAc=4:1) to obtain 100mg of solid (residue contains 13% 22, 23 olefins). 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 in vacuo and purged with H2 several times. The mixture was stirred for 2 hrs at 25 °C under H2. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by SFC (column: C2 250 mm*30 mm, 10 um), 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.

[0847] 1 H NMR (400MHz, CDCl3) δ5.40-35 (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).

[0848] LCMS Rt = 1.202 min, 2.0 min chromatography, 30-90AB, 100% purity, MS ESI C 26 H 40 F3O[M+H-H2O] - The calculated value is 425, and the measured value is 425.

[0849] Example 27: Synthesis of 2706 and 2707

[0850]

[0851] The experimental procedure for intermediate ST-200-CF3_4A can be found in Example 3. ST-200-35-7 can be found in Example 19. The stereochemistry of 2707 was confirmed by X-ray.

[0852] Synthetic ST-200-35-8A / 8B

[0853]

[0854] 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 for 1 h at 0 ° C. Water (10 mL) was added to the mixture at 0 ° C and extracted with DCM (3x10 mL). The organic layer was washed with 1M HCl (10 mL), saturated Na2CO3 (10 mL) and brine. The mixture was dried over anhydrous Na2SO4 and concentrated in vacuo to obtain a residue. The residue was purified by prep-TLC (PE / EA=5 / 1) to obtain a mixture. The mixture was separated twice by SFC (instrument: MG-II; method: column: AD (250 mm*30 mm, 5 um); condition: 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), which is ST-200-35-8B (44 mg, 12%) and peak 2 (Rt=5.766 min) ST-200-35-8A (38 mg, 10%), both as solids.

[0855] ST-200-35-8B:

[0856] SFC Rt = 5.134 min, 10.0 min chromatography, AD_3_EtOH_DEA_5_40_25ML, 100% de.

[0857] ST-200-35-8A:

[0858] Synthesis 2706

[0859]

[0860] 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 Na SO , filtered, concentrated in vacuo and triturated from MeCN (1 mL) to give 2706 (24 mg, 66%) as a solid.

[0861] 1 H NMR (400MHz, CDCl3) δ4.02 (q, J=8.0Hz, 1H), 3.93-3.83 (m, 1H), 3.69 (d, J=9.2Hz, 1H), 3.55 (d, J=9.2Hz, 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).

[0862] HPLC Rt = 3.97 minutes, 8.0 minutes chromatography, 50-100_AB_E, purity 100%.

[0863] MS MS ESI C 28 H 44 F3O2[M+H-H2O] + The calculated value is 469.3288, and the measured value is 469.3244.

[0864] Synthesis 2707

[0865]

[0866] MeOH (0.2 mL), water (0.2 mL) and LiOH.H2O (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 Na2SO4, filtered, concentrated in vacuo and triturated from MeCN (1 mL) to give 2707 (21 mg, 67%) as a solid.

[0867] 1H 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 mm AB, 100% purity.

[0868] MS MS ESI C 28 H 44 F3O2[M+H-H2O] + The calculated value is 469.3288, and the measured value is 469.3244.

[0869] Example 28: Synthesis of E-2817

[0870]

[0871] The synthesis of ST-200-CF3_6C can be found in Example 5.

[0872] Synthesis of ST-200-43-4_2.

[0873] To a suspension of t-BuOK (3.53 g, 31.6 mmol) in THF (30 mL) was added Me3SI (4.18 g, 20.5 mmol) at 15°C under N2. The suspension was stirred at 15°C for 30 minutes. To this mixture was added dropwise a solution of 200-DA-E31_1A (2 g, 15.8 mmol) in 10 ml of THF at 15°C. The mixture was stirred at 15°C for 16 hours. The mixture was quenched with sat.NH4Cl (100 mL) and extracted with EtOAc (3 x 150 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo to give 200-DA-E31_1 (1.8 g, 81%) as a liquid.

[0874] 1 H NMR (400MHz, CDCl3) δ2.58 (s, 2H), 1.90-1.80 (m, 1H), 1.70-1.55 (m, 2H), 1.54-1.45 (m, 3H), 1.40-1.30 (m, 2H), 1.00-0.90 (m, 6H).

[0875] Synthesis of ST-200-3CF3-A18_1

[0876]

[0877] First, n-BuLi (0.5mL, 2.5M in hexane, 1.25mmol) is added to THF (0.5mL). A solution of ST-200-CF3_6C (250mg, 0.4746mmol) in THF (3mL) is added at -70°C. The mixture is stirred for 1h at -70°C. ST-200-43-4_2 (133mg, 0.9492mmol) is added at -70°C. The mixture is stirred for another 1h at -70°C. The mixture is warmed to 25°C and stirred for 16 hours. The reaction mixture is quenched by adding NH4Cl (50mL, saturated aqueous solution) and extracted with EtOAc (2x30mL). The organic layer is separated, dried over Na2SO4, filtered, and concentrated to obtain ST-200-3CF3-A18_1 (390mg, crude material), which is a solid, which is directly used in the next step.

[0878] Synthetic E-2817

[0879]

[0880] The solution of ST-200-3CF3-A18_1 (390mg, 0.5847mmol) in MeOH (25mL) is heated at 60 ℃.Mg powder (500mg, 20.8mmol) is added in four parts at 60 ℃. The mixture is stirred for 1h at 60 ℃. The mixture is quenched with HCl (50mL, 2M) until the reaction becomes clear and extracted with DCM (2x50mL). The organic phase merged is used Na2SO4 dry, filtered, concentrated and purified by flash column (0-10% EtOAc in PE) to obtain 135mg solid. Impure product is purified by flash column (0-20% EtOAc in PE) to obtain E-2817 (101mg, 75%), which is a solid.

[0881] 1 H NMR (CDCl3, 400MHz) δ2.08-2.03 (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).

[0882] LCMS Rt = 1.463 min, 2 min chromatography, 30-90AB, purity 100%, MS ESI C32 H 52 Calculated value of F3O[M+H-H2O]+ 509, found 509.

[0883] Example 29: Synthesis of 2918

[0884]

[0885] The synthesis of ST-200-CF3_6C can be found in Example 5.

[0886] Synthesis of ST-200-3CF3-A8_1

[0887]

[0888] At -78 DEG C under N2, the suspension of ST-200-CF3-6C (250mg, 0.475mmol) in THF (2.5mL) was added dropwise to a solution of n-BuLi (568 μL, 2.5M in hexane, 1.42mmol) in THF (0.5mL). The mixture was stirred at -78 DEG C for 30 minutes. A solution of 2-(trifluoromethyl)oxirane (79.7mg, 0.712mmol) was added dropwise at -78 DEG C. The mixture was stirred for another 30 minutes, then gradually warmed to 25 DEG C. The reaction mixture was stirred at 25 DEG C for 16 hours. The reaction mixture was quenched with saturated NH4Cl aqueous solution (30mL) and extracted with ethyl acetate (3x20mL). The combined organic phases were washed with brine (30 mL), dried over Na 2 SO 4 , 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.

[0889] Synthesis 2918

[0890]

[0891] 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 for 1 h at 60 ° C. The mixture was quenched with HCl (50 mL, 1 N) until the reaction became clear and extracted with DCM (2x30 mL). The organic phases merged were dried with Na SO , filtered, concentrated, and purified by flash column (0-10% EtOAc in PE) to obtain 63 mg of solid, which was ground from DCM and hexane to obtain 291 g (5 mg, 2%).

[0892] 1H NMR (CDCl3, 400MHz) δ3.90-3.80 (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).

[0893] LCMS Rt = 1.219 minutes, 2 minutes of chromatography, 30-90AB, purity 100%.

[0894] Example 30: Synthesis of 3035

[0895]

[0896] The experimental steps of intermediate ST-200-CF3_4A can be found in Example 3.

[0897] Synthesis of tosylate:

[0898]

[0899] At 0 DEG C to LiAlH4(45.3g, 1.26mol) suspension in THF(1L) was added dropwise a solution of 7330_3S(100g, 632mmol) in THF(500mL) and the internal temperature was raised to about 50 DEG C. After addition, the mixture was stirred at 70 DEG C for 16 hours. The mixture was quenched with HCl(1L, 3M aq.) to pH=2 and extracted with MTBE(3x500mL). The organic phases merged were dried with Na2SO4, filtered and concentrated under reduced pressure (<40 DEG C) to obtain 7330_4S(92g, crude material), which was an oil.

[0900] 1 H NMR (400MHz, 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).

[0901] 4-Methylbenzene-1-sulfonyl chloride (98.9 g, 519 mmol) was added in batches to a solution of 7330_4S (50 g, 346 mmol) in pyridine (300 mL) at 0 ° C within 5 minutes. The reaction solution was stirred at 20 ° C for 16 hours. The reaction mixture was quenched with 2NHCl (400 mL) at 0 ° C to pH = 1-2. The internal temperature was kept below 30 ° C and the mixture was extracted with MTBE (3x200 mL). The combined organic layers were dried with Na SO , filtered, concentrated and purified by column (0-10% EtOAc in PE) to obtain 7330_5S (93 g, 90%, 99.42% ee), which was an oil.

[0902] 1 H NMR (400MHz, CDCl3) δ7.79 (d, J=7.6Hz, 2H), 7.37 (d, J=8.0Hz, 2H), 4.13-4.03 (m, 2H), 2.99 (s, 1H), 2.46 (s, 3H), 1.37 (s, 3H),

[0903] LCMS Rt = 1.103 min, 2.0 min chromatography, 10-80AB, 100% purity, MS not checked.

[0904] Synthesis of ST-200-3CF3-C11S_1

[0905]

[0906] At -70 DEG C under N2, a suspension of ST-200-CF3_4A (250mg, 0.48mmol) in THF (4mL) was added dropwise to a solution of n-BuLi (0.48mL, 2.5M in hexane, 1.19mmol) in THF (1mL). After stirring at -70 DEG C for 30 minutes, diisopropylamine (120mg, 1.19mmol) was added dropwise at -70 DEG C, followed by addition of (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropyl 4-methylbenzenesulfonate (212mg, 0.71mmol) at -70 DEG C. The mixture was stirred for another 30 minutes, then gradually warmed to 25 DEG C. The reaction mixture was stirred at 25 DEG C for 24 hours. The reaction mixture was quenched with saturated NH4Cl aqueous solution (5mL), extracted with EtOAc (3x10mL). The combined organic phases were washed with brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo to give ST-200-3CF 3 -C 11 S — 1 (480 mg, crude) which was used directly.

[0907] Synthesis 3035

[0908]

[0909] Under N2, Mg powder (705 mg, 29.4 mmol) and NiCl2 (1 mg, 0.007 mmol) were added to a solution of ST-200-3CF3-C11S_1 (480 mg, 0.74 mmol) in 50 mL of anhydrous MeOH at 60 ° C. The reaction mixture was quenched with 2M HCl (10 mL) until the solid dissolved. The mixture was extracted with EtOAc (3x20 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 purification (0-20% EtOAc in PE) to obtain a crude product, which was further purified by recrystallization from MeCN (10 mL) at 85 ° C to obtain 3035 (53 mg, 21%) as a solid.

[0910] 1 H NMR (400MHz, CDCl3) δ5.41-5.34 (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 minutes, 2 minutes chromatography, 30-90AB_2MIN_E, purity 99%.

[0911] Example 31: Synthesis of 3149

[0912]

[0913] The experimental steps of intermediate ST-200-CF3_4A can be found in Example 3.

[0914] Synthesis of ST-200-3CF3_C8R_1

[0915]

[0916] At -65 DEG C under N2, the suspension of ST-200-CF3-4A (250mg, 0.476mmol) in THF (2.5mL) is added dropwise to a solution of n-BuLi (0.568mL, 2.5M in hexane, 1.42mmol) in THF (0.5mL). After adding diisopropylamine (143mg, 1.42mmol) and stirring at -65 DEG C for 30 minutes, a solution of (R)-2-(trifluoromethyl)oxirane (63.9mg, 0.571mmol) is added dropwise at -65 DEG C. The mixture is stirred for another 30 minutes, then gradually warmed to 25 DEG C. Reactant mixture is stirred at 25 DEG C for 16 hours. Reactant mixture passes through saturated NH4Cl aqueous solution (30mL) is quenched and extracted with ethyl acetate (3x20mL). The combined organic phases were washed with brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo to give ST-200-3CF 3 -C 8 R_1 (250 mg, crude) as a solid which was used directly in the next step.

[0917] Synthesis 3149

[0918]

[0919] 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 anhydrous methanol (50 mL) at 50 ° C under N2. Upon addition of Mg, the mixture was stirred to initiate continuous hydrogen generation. The reaction mixture was then stirred at 60 ° C for 1 hour. The reaction mixture was quenched with 2M HCl (100 mL) added dropwise at 10 ° C until the solid dissolved. After extraction with EtOAc (2x150 mL), the combined organic layers were washed with saturated NaHCO3 aq. (300 mL), brine (300 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain a solid, which was purified by silica gel chromatography (PE / THF=4 / 1) to obtain a crude product, which was recrystallized from MeCN (10 mL) to obtain an impure product (30 mg, 15%). The impure product (30 mg, 0.068 mmol) was purified by SFC (column: AD 250 mm*30 mm, 10 um), gradient: 20-20% B (A=0.1% NH3 / H2O, B=EtOH), flow rate: 60 mL / min) to give 3149 (12 mg, 40%) as a solid.

[0920] 1H NMR (400MHz, CDCl3) δ5.40-5.35(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).

[0921] HPLC Rt = 6.25 minutes, 1.2 minutes chromatography, 30-90AB, purity 98%.

[0922] HRMS ESI C 26 H 39 F6O2[M+H] - The calculated value is 497.2849, and the measured value is 497.2842.

[0923] Example 32: Synthesis of 3266

[0924]

[0925] The experimental steps of intermediate ST-200-CF3_4A can be found in Example 3.

[0926] Synthesis of ST-200-3CF3-C7R_1

[0927]

[0928] At -65 ℃ under N 2, the suspension of ST-200-CF 3 -4A (250mg, 0.476mmol) in THF (4mL) is added dropwise to a solution of n-BuLi (568mL, 2.5M in hexane, 1.42mmol) in THF (1mL). After stirring at -65 ℃ for 30 minutes, diisopropylamine (143mg, 1.42mmol) is added at -65 ℃. Then, (R) -2- methyloxirane (82.4mg, 1.42mmol) is added dropwise at -65 ℃. The mixture is stirred for another 30 minutes, then gradually warmed to 25 ℃. Reactant mixture is stirred at 25 ℃ for 16 hours. The reaction is saturated with NH 4 Cl aq. (50mL) is quenched, extracted with EtOAc (3x50mL). The organic layer merged is used Na 2 SO 4 is dried, filtered and concentrated to obtain crude product, which is a solid, which is directly used in the next step.

[0929] Synthesis 3266

[0930]

[0931] 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 anhydrous methanol (20 mL) at 50 ° C under N2 with stirring. After stirring at 60 ° C for 1 hour, the mixture was quenched with HCl (50 mL, 1 N) until the reaction became clear and extracted with EtOAc (3 x 30 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column purification (0-15% EtOAc in PE) to obtain an impure product (100 mg, 0.225 mmol, impure, containing 13% 22,23 olefins). Lindlar catalyst (200 mg, 0.225 mmol) was added to a solution of the impure product in THF (20 mL) under N2. The mixture is vacuum degassed and purged several times with H2.At 25 ℃, the mixture is stirred for 2 hours.Reactant mixture is filtered through diatomaceous earth pad and washed with THF (3x10mL).Filtrate is concentrated to obtain impure product, it is ground 2 hours to obtain impure product at 68 ℃ from normal hexane (10mL), and it is solid.Impure product passes through silica gel chromatography purification (PE / EtOAc=0 to 5 / 1) to obtain 3266 (48mg, impure), it is solid, it passes through SFC purification (post: AD (150 × 4.6mm, 3um), gradient: 5%-40%B (A: CO2 B: ethanol) flow velocity: 2.5mL / min) to obtain 3266 (10mg), it is solid.

[0932] 1 H NMR (400MHz, CDCl3) δ5.40-5.33.(m, 1H), 3.78-3.65(m, 1H), 2.52-2.45(m, 2H), 2.08 -1.65(m, 7H), 1.58-1.32(m, 7H), 1.32-1.23(m, 4H), 1.23-0.75(m, 16H), 0.68(s, 3H).

[0933] LCMS Rt = 1.149 min, 2.0 min chromatography, 30-90AB, 100% purity, MS ESI C 26 H 40 F3O[M+H-H2O] + The calculated value is 425, and the measured value is 425.

[0934] Example 33: Synthesis of 3382

[0935]

[0936] Stereochemistry was assigned based on the synthesis of chiral epoxides, the synthesis of which is described in Example 35.

[0937] The experimental steps of intermediate ST-200-CF3_4A can be found in Example 3.

[0938] Synthetic ST-200-31-6_1

[0939]

[0940] At-70 ℃ under N2, the suspension of ST-200-CF3-4A (500mg, 0.95mmol) in THF (4mL) is added dropwise to a solution of n-BuLi (0.95mL, 2.5M in hexane, 2.38mmol) in THF (1mL). After stirring at-70 ℃ for 30 minutes, at-70 ℃, a solution of diisopropylamine (240mg, 2.38mmol) is added dropwise, then at-70 ℃, a solution of 2-(tert-butyl) oxirane (142mg, 1.42mmol) is added dropwise. The mixture is stirred for another 30 minutes at-70 ℃, then gradually warmed to 25 ℃. After stirring at 25 ℃ for 24 hours, the reaction mixture is quenched by saturated NH4Cl aqueous solution (5mL), extracted with EtOAc (3x20mL). The combined organic phases were washed with brine (40 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo to give ST-200-31-6_1 (650 mg, crude material), which was used directly.

[0941] Synthetic ST-200-31-6

[0942]

[0943] Under N2, at 60 ℃, Mg powder (998mg, 41.6mmol) and NiCl2 (5mg, 0.05mmol) are added to a solution of ST-200-31-6 (650mg, 1.04mmol) in 100mL anhydrous MeOH under stirring. The reaction mixture is quenched by 2M HCl (50mL) until the solid dissolves. The mixture is extracted with EtOAc (3x100mL). The combined organic layer is washed with saturated NaHCO3 (150mL), brine (150mL), and dried over Na2SO4, filtered and concentrated. The residue is purified by flash column (0~15% EtOAc in PE) to obtain impure ST-200-31-6, which is a solid. Under N2, Lindlar catalyst (200mg) is added to a solution of ST-200-31-6 in EtOAc (10mL). The suspension is vacuum degassed and purged three times with H2. The solution was then hydrogenated under 15 psi hydrogen at 25° C. for 4 h. The mixture was filtered through a pad of celite and washed with EtOAc (3×10 mL). The filtrate was concentrated and concentrated to give ST-200-31-6 (210 mg, 43%) as a solid.

[0944] 1 H NMR (400MHz, CDCl3) δ5.39-5.34(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).

[0945] Synthesis 3382

[0946]

[0947] 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 / H2O, B=EtOH), flow rate: 50 mL / min) to give 3382 (90 mg, 43%) as a solid.

[0948] 1H NMR (400MHz, CDCl3) δ5.42-5.34 (m, 1H), 3.19-3.12 (m, 1H), 2.48 (s, 2H), 2.09-1.6 7(m, 8H), 1.53-1.23(m, 12H), 1.22-0.98(m, 8H), 0.95-0.84(m, 12H), 0.69(s, 3H).

[0949] LCMS Rt = 1.440 min, 2 min chromatography, 30-90AB_2MIN_E, purity 100%, MS ESIC 29 H 46 F3O[M+H-H2O] + The calculated value is 467, and the measured value is 467.

[0950] SFC_E1 Rt = 4.337 min, 10 min chromatography, AD_3_EtOH_DEA_5_40_25 mL, purity: 100%.

[0951] Example 34: Synthesis of 3495 and 3496

[0952]

[0953] The stereochemistry of 3496 was determined by X-ray data. The experimental procedure for intermediate ST-200-CF3_4A can be found in Example 3.

[0954] Synthesis 200-DA-C24_8_2

[0955]

[0956] At 0 ℃ under N 2, sodium hydride (5.98g, 60% in mineral oil, 150mmol) is added in batches to a mixture of trimethylsulfonium iodide (30.6g, 150mmol) in THF (100mL). The mixture is stirred at 0 ℃ for 30 minutes. A solution of dihydrofuran-3 (2H) -one (10g, 116mmol) in DMSO (100mL) is added dropwise at 0 ℃. The reaction mixture is stirred at 0 ℃ for 2 hours. The mixture is poured into ice-water (500mL) in batches and extracted with DCM (2x500mL). The organic phase merged is washed with salt water (500mL), used Na 2 SO 4 is dried, filtered and concentrated to obtain 200-DA-C24_8_2 (4g, crude material, 34%), which is an oil at 18 ℃, which is directly used in the next step.

[0957] Synthesis of ST-200-CF3_8

[0958]

[0959] At -70 ℃, butyllithium (2.71mL, 2.5M in n-hexane, 6.79mmol) is added to a solution of diisopropylamine (714mg, 7.33mmol) in THF (3mL). The mixture is warmed to 0 ℃ and stirred at 0 ℃ for 30 minutes. The mixture is cooled to -70 ℃ and a solution of 200-DA-C24_8_2 (300mg, 2.99mmol) in THF (2mL) is added. The mixture is stirred at -70 ℃ for 1h. A solution of ST-200-CF3_4A (1.42g, 2.71mmol) in THF (2mL) is added at -70 ℃. The mixture is warmed to 25 ℃ and stirred at this temperature for 16 hours. The mixture is quenched with Sat NH4Cl (10mL). The mixture is extracted with EtOAc (2x10mL). The organic phase was washed with brine (2 x 10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash column (0-50% EtOAc in PE) to give ST-200-CF3_8 (280 mg, 17%) as a solid which was used directly in the next step.

[0960] Synthesis of compound 10

[0961]

[0962] Under N2, nickel chloride (II) (580 μ g, 4.48 μ mol) and Mg powder (435 mg, 17.9 mmol) are added into ST-200-CF3-8 (280 mg, 0.448 mmol) in 50 mL of anhydrous methanol in four parts at 60 ° C. The reaction mixture is quenched by the 1M HCl (150 mL) added dropwise until the solid dissolves. After extraction with EtOAc (3x50 mL), the organic layer is washed with saturated NaHCO3 (50 mL), salt solution (50 mL), and Na2SO4 is dried, filtered and concentrated. The residue is purified by flash column purification (0~20% EtOAc in PE) to obtain compound 10 (210 mg, 97%), which is a solid.

[0963] 1 H NMR CDCl3 400MHz δ5.39-5.35 (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).

[0964] Synthesis of 3495 and 3496

[0965]

[0966] 10 (280 mg, 0.577 mmol) was purified by SFC (column: AS (250 mm*30 mm, 5 um), gradient: 20-20% B (A=0.1% NH3 / H2O, B=EtOH), flow rate: 60 mL / min) to give solid 3495 (20 mg, 7%) and solid 3496 (32 mg, 11%). 3495

[0968] 1 H NMR CDCl3 400MHz δ5.39-5.35 (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).

[0969] LCMS Rt = 1.081 min, 2.0 min chromatography, 30-90AB_2MIN_E.M, purity 100%, MS ESIC 28 H 42 F3O2[M+H-H2O] + The calculated value is 467, and the measured value is 467. 3496

[0971] 1 H NMR CDCl3 400MHzδ5.39-5.35(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).

[0972] LCMS Rt = 1.095 min, 2.0 min chromatography, 30-90AB_2MIN_E.M, purity 100%, MS ESIC 28 H 42 F3O2[M+H-H2O] + The calculated value is 467, and the measured value is 467.

[0973] Example 35: Synthesis of 3507

[0974]

[0975] Stereochemistry was assigned based on the synthesis of chiral epoxides.

[0976] The experimental steps of intermediate ST-200-31-6 can be found in Example 33.

[0977] Synthetic ST-200-31-5

[0978]

[0979] 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 / H2O, B=EtOH), flow rate: 50 mL / min to give impure 3507 (100 mg, 45%) as a solid.

[0980] 1 H NMR (400MHz, CDCl3) δ5.42-5.33 (m, 1H), 3.15-3.06 (m, 1H), 2.48 (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).

[0981] Synthesis 3507

[0982]

[0983] Under N2, Lindlar catalyst (100mg) is added to a solution of impure sample (100mg, 0.21mmol, comprising 22,23-alkene) in EtOAc (5mL). The suspension is vacuum degassed and purged three times with H2. The solution is then hydrogenated at 25°C for 4h under 15psi hydrogen. The mixture is filtered through a celite pad and washed with EtOAc (3x10mL). The filtrate is concentrated to obtain a solid. 1H NMR shows that there are still 12.5% ​​22,23-olefins contained. Impure 3507 is dissolved in THF / MeOH (3 / 3mL) and treated with Lindlar (100mg) under N2. The suspension is vacuum degassed and purged three times with H2. The solution is then hydrogenated at 25°C for 4h under 15psi hydrogen. The mixture is filtered through a celite pad and washed with THF (3x10mL). The filtrate is concentrated and ground from PE (5mL) to obtain 3507, which is a solid. This is ground in n-hexane (5mL) at 25°C to obtain 3507 (40mg, 40%), which is a solid. 1 H NMR (400MHz, CDCl3) δ5.42-5.34(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=6.4Hz, 3H), 0.89(s, 9H), 0.68(s, 3H).

[0984] LCMS Rt = 1.298 min, 2 min chromatography, 30-90AB_2MIN_E, purity 100%, MS ESIC 29 H 46 F3O[M+H-H2O] + The calculated value is 467, and the measured value is 467.

[0985] SFC_E1 Rt = 3.887 min, 10 min chromatography, AD_3_EtOH_DEA_5_40_25ML, 100% de.

[0986] Synthesis of 3507 and 3634 confirming their stereochemistry

[0987]

[0988] To THF solution (0.5mL) is added n-BuLi (0.8mL, 2.5M in hexane, 2mmol), at -70 ℃, add a solution of DD (420mg, 0.8mmol) in THF (2mL). After stirring 1h at -70 ℃, at -70 ℃, add a solution of (R)-2-(tert-butyl) oxirane (120mg, 1.2mmol) in THF (0.5mL). The mixture is stirred for 1h at -70 ℃ and is warmed to 25 ℃ and stirred for 16 hours. The reaction mixture is quenched with saturated NH4Cl (10mL) and extracted with EtOAc (2x5mL). The organic layer is separated, dried over anhydrous Na2SO4, filtered and concentrated. Residue (400mg) is directly used in the next step.

[0989] To a mixture of DDA (400 mg, crude material) in MeOH (30 mL) was added NiCl2 (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 batches. The reaction was quenched with HCl (1 M, 10 mL) and the mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, 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 / H2O IPA, B=EtOH), flow rate: 50 mL / min) to give 3507 (100 mg) as a solid.

[0990] 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, 30-90 AB_2MIN_E, purity 100%, MS ESI C 29 H 46 F3O[M+H-H2O] + The calculated value is 467, and the measured value is 467.

[0991] SFC Rt = 3.804 min, 10 min chromatography, AD_3_EtOH_DEA_5_40_25ML, 100% de.

[0992] To a solution of 3507 (70 mg) in THF (10 mL) was added Pd(OH)2 / C (20%, dried, 100 mg). The mixture was stirred at 50°C under H2 (50 psi) 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.

[0993] 1 H NMR (400MHz, CDCl3) δ3.17-2.98 (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).

[0994] LCMS Rt = 1.349 min, 2.0 min chromatography, 30-90_AB_E, 100% purity, no MS signal.

[0995] MS MS ESI C 29 H 48 F3O[M+H-H2O] + The calculated value is 469, and the measured value is 469.

[0996] Example 36: Synthesis of 3634

[0997]

[0998] The experimental steps of intermediate 3507 can be found in Example 3.

[0999] Synthesis 3634

[1000]

[1001] To a solution of 3507 (70 mg) in THF (10 mL) was added Pd(OH)2 / C (20%, dried, 100 mg). The mixture was stirred at 50°C under H2 (50 psi) 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.

[1002] 1H NMR (400MHz, CDCl3) δ3.17-2.98 (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).

[1003] LCMS Rt = 1.349 min, 2.0 min chromatography, 30-90_AB_E, 100% purity, no MS signal.

[1004] MS MS ESI C 29 H 48 F3O[M+H-H2O] + The calculated value is 469, and the measured value is 469.

[1005] Example 37: Synthesis of 3788

[1006]

[1007] The experimental steps of intermediate ST-200-31-4 can be found in Example 33.

[1008] Synthesis 3788

[1009]

[1010] Pd (OH) / C (100 mg) is added to a solution of ST-200-31-4 (60 mg, 0.12 mmol) in THF / MeOH (5 mL / 5 mL) and the mixture is degassed and back-filled three times with H. The reaction is then stirred at 50 ° C under 50 psi H for 16 h. The reaction mixture is filtered through a celite pad and washed with EtOAc (100 mL). The filtrate is concentrated to obtain impure ST-200-31-3B, which is a solid. Pd (OH) / C (50 mg) is added to a solution of impure ST-200-31-4 in THF / MeOH (3 mL / 3 mL) and the mixture is degassed and back-filled 3 times with H. The reaction is then stirred at 50 ° C under 50 psi H for 72 h. The reaction mixture is filtered through a celite pad and washed with EtOAc (100 mL). The filtrate was concentrated to give 40 mg of crude product, which was triturated in n-hexane (2 x 3 mL) to give 3788 (7 mg, 17%) as a solid.

[1011] 1H NMR (400MHz, CDCl3) δ3.19-3.08 (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).

[1012] LCMS Rt = 1.313 min, 2.0 min chromatography, 30-90AB_2MIN_E, purity 98%, MS ESIC 29 H 48 F3O[M+H-H2O] + The calculated value is 469, and the measured value is 469.

[1013] Example 38: Synthesis of 3877 and 3886

[1014]

[1015] The stereochemistry of 3877 is shown below; it was assigned by NMR.

[1016] Synthetic ST-200-74-5_1

[1017]

[1018] Under N2, at 35 DEG C by Me3SI (4.71g, 23.1mmol) is added to the suspension of t-BuOK (3.98g, 35.6mmol) in THF (40mL).After stirring at 35 DEG C for 30mins, a solution of ST-200-74-5_1 (2g, 17.8mmol) is added dropwise at 35 DEG C. The mixture is stirred at 35 DEG C for 16hrs, quenched with sat.NH4Cl (50mL) and extracted with EtOAc (3x50mL). The organic phase merged is dried with Na2SO4, filtered and concentrated in vacuo to obtain ST-200-74-5_2 (1.8g, thick material), which is a liquid, which is directly used in the next step.

[1019] Synthetic ST-200-74-5_3

[1020]

[1021] n-BuLi (0.948mL, 2.5M in hexane, 2.37mmol) is added to THF (5mL).At-70 ℃, add the solution of ST-200-CF3-6C (500mg, 0.949mmol) in THF (15mL).After stirring 1h at-70 ℃, add 6-methyl-1-oxaspiro [2.5] octane (358mg, 2.84mmol) at-70 ℃.The mixture is stirred for 1 hour at-70 ℃, then warmed to 15 ℃ and stirred 16 hours.After quenching with NH4Cl (50mL), the mixture is extracted with EtOAc (2x30mL). The organic layer was separated, dried over Na 2 SO 4 , filtered, concentrated, and purified by combi-flash (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.

[1022] Synthesis 3877

[1023]

[1024] The solution of ST-200-74-5_3 (350mg, 0.536mmol) in MeOH (30mL) is heated at 65 ℃.At 65 ℃, add Mg powder (513mg, 21.4mmol) once.Mixture is refluxed for 1h at 65 ℃.Mixture is quenched with HCl (40mL, 2N) until reaction becomes clear and extracts with DCM (2x30mL).The organic layer Na 2 SO 4 that merges is dried, filtered, concentrated and passed through silica gel chromatography purifying (0-12% EtOAc in PE) to obtain 3877 (12mg, 4%), it is solid. 3877:

[1026] 1 H NMR (400MHz, CDCl3) δ2.11-1.90 (m, 3H), 1.89-1.74 (m, 2H), 1.73-1.58 (m, 5H), 1.53-1.4 3(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).

[1027] LCMS Rt = 1.728 minutes, 2 minutes of chromatography, 30-90AB_2MIN_E, purity 100%.

[1028] MS ESI scan (2.939-3.092 min, 10 scans) Frag = 50.0 V, 80-100 Å / min.m, MS ESI C 31H 51 F3O2Na[M+Na] + The calculated value is 535, and the measured value is 535.

[1029]

[1030] Synthetic ST-200-096-011A / B

[1031]

[1032] To the solution of ST-200-74-5_3 (700mg, 1.07mmol) in MeOH (40mL) at 65 ℃, disposable addition NiCl (27.6mg, 0.214mmol) and Mg powder (1.02g, 41.8mmol) is added. The mixture is stirred at 65 ℃ for 10 minutes. The disposable addition extra Mg powder (513mg, 22.3mmol) is added. After stirring at 65 ℃ for 10 minutes, the mixture is quenched with HCl (200mL, 1N) and extracted with EtOAc (3x50mL). The organic phase Na merging is dried, filtered, concentrated and by combi-flash purification (0-15% EtOAc in PE) to obtain ST-200-096-011A (63mg, 11%, peak 1) and ST-200-096-011B (114mg, 20%, peak 2), it is solid. 3877

[1034] 1 H NMR (400MHz, CDCl3) δ2.09-1.93(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).

[1035] LCMS Rt = 1.391 minutes, 2 minutes of chromatography, 30-90AB_2MIN_E, purity 100%.

[1036] MS ESI scan (1.955-2.16 min, 8 scans) Frag = 50.0 V, 80-100 Å / min.m, MS ESI 31 H 51 Calculated value of F3O2Na [M+Na] + 535, measured value 535.

[1037] 1H NMR (400MHz, CDCl3) δ2.09-2.00 (m, 2H), 1.99-1.89 (m, 1H),

[1038] 1.87-1.76(m, 2H), 1.71-1.61(m, 3H), 1.55-0.42(m, 10H), 1.41-1.19(m, 1 3H), 1.14-0.96 (m, 6H), 0.95-0.86 (m, 7H), 0.84 (s, 3H), 0.72-0.62 (m, 4H).

[1039] LCMS Rt = 1.450 minutes, 2 minutes of chromatography, 30-90AB_2MIN_E, purity 100%.

[1040] MS ESI scan (1.938-2.617 min, 9 scans) Frag = 50.0 V, 80-100 mm / s, MS ESI 31 H 51 F3O2Na[M+Na] + The calculated value is 535, and the measured value is 535.

[1041] Example 39: Synthesis of 3983

[1042]

[1043] See Example 5 for the synthesis of ST-200-CF3_6C.

[1044] Synthetic ST-310-15-2_2

[1045]

[1046] By Me3SI (13.6g, 66.7mmol) and t-BuOK (17.8mL, 5M in THF, 89.0mmol) in DMSO (100mL) solution is stirred and heated at 25 ℃ under N2 for 30 minutes.Cycloheptanone (5g, 44.5mmol) is added to the reaction mixture and stirred at 25 ℃ for 3 hours.The reaction is treated with water (300mL), extracted with EtOAc (2x100mL).The organic phase merged is washed with water (2x300mL), brine (2x300mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to obtain ST-200-74-5_2 (4g, 71%), which is a liquid.

[1047] 1 H NMR (400MHz, CDCl3) δ2.59 (s, 2H), 1.72-1.50 (m, 12H).

[1048] Synthesis of ST-310-15-2_3

[1049]

[1050] At -70 DEG C under N2, n-BuLi (0.568mL, 1.42mmol, 2.5M in hexane) is added to a solution of ST-200-CF3_6C (300mg, 0.569mmol) in THF (3mL). After being cooled to -70 DEG C, 1-oxaspiro [2.6] nonane (107mg, 0.853mmol) is added. The reaction is warmed to 25 DEG C and stirred at 25 DEG C for 12 hours. The reaction is quenched with NH4Cl (10mL, saturated aqueous solution), water (50mL) and extracted with EtOAc (3x10mL). The organic phase merged is concentrated to obtain residue, which is purified by silica gel chromatography (PE / EtOAc=10 / 1~5 / 1) to obtain compound ST-200-74-6_3 (200mg, impure), which is an oily matter. The crude mixture is directly used in the next step.

[1051] Synthesis 3983

[1052]

[1053] The solution of ST-200-74-6_3 (200mg, 306umol) in MeOH (50mL) is heated to 60 ℃.Add Mg powder (371mg, 15.3mmol) in four parts at 60 ℃.After stirring 1h at 60 ℃, ...

Claims

1. Compound of formula (I-59): or a pharmaceutically acceptable salt thereof, wherein: R 2 and R 3 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic group, or R 2 and R 3 , together with the carbon atoms to which they are attached, form a substituted or unsubstituted 3-8 membered ring; R 4 and R 5 are independently hydrogen, halogen or -OR C , where R C is hydrogen or substituted or unsubstituted C1-C6 alkyl, or R 4 and R 5 , together with the carbon atom to which they are attached, form an oxo group; R 6 is absent or is hydrogen; and represents a single bond or a double bond, where When one of them is a double bond, the other is a single bond; when two When both are single bonds, R 6 is hydrogen; and when When one of them is a double bond, R 6 does not exist; Provided that the following compounds are not included:

2. Compound of formula (I-66): or a pharmaceutically acceptable salt thereof, wherein: R 1 is a substituted or unsubstituted C1-C6 alkyl group; R 2 is substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 3 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, aryl, or substituted or unsubstituted heteroaryl; R 4 and R 5 are independently hydrogen, halogen or -OR C , where R C is hydrogen or unsubstituted or substituted C1-C3 alkyl, or R 4 and R 5 , together with the carbon atom to which they are attached, form an oxo group; R 6 is absent or is hydrogen; and represents a single bond or a double bond, where When one of them is a double bond, the other is a single bond; when two When both are single bonds, R 6 is hydrogen; and when When one of them is a double bond, R 6 Does not exist.

3. Compound of formula (I-61): or a pharmaceutically acceptable salt thereof, wherein: R 1 is hydrogen or substituted or unsubstituted C1-C6 alkyl; R 2 and R 3 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, or R 2 and R 3 , together with the carbon atoms to which they are attached, form a substituted or unsubstituted 3-8 membered ring; R 4 and R 5 are independently hydrogen, halogen or -OR C , where R C is hydrogen or substituted or unsubstituted C1-C6 alkyl, or R 4 and R 5 , together with the carbon atom to which they are attached, form an oxo group; R 6 is absent or is hydrogen; and represents a single bond or a double bond, where When one of them is a double bond, the other is a single bond; when two When both are single bonds, R 6 is hydrogen; and when When one of them is a double bond, R 6 does not exist; Provided that the following compounds are not included:

4. Compound of formula (I-62): or a pharmaceutically acceptable salt thereof, wherein: R 1 is hydrogen or substituted or unsubstituted C1-C6 alkyl; R 2 and R 3 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclic, or R 2 and R 3 , together with the carbon atoms to which they are attached, form a substituted or unsubstituted 3-8 membered ring; R 4 and R 5 are independently hydrogen, halogen or -OR C , where R C is hydrogen or substituted or unsubstituted C1-C6 alkyl, or R 4 and R 5 , together with the carbon atom to which they are attached, form an oxo group; R 6 is absent or is hydrogen; and represents a single bond or a double bond, where When one of them is a double bond, the other is a single bond; when two When both are single bonds, R 6 is hydrogen; and when When one of them is a double bond, R 6 Does not exist.

5. Compound of formula (I-60): or a pharmaceutically acceptable salt thereof, wherein: R 2 and R 3 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted carbocyclic group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, or substituted or unsubstituted heteroaryl group, or R 2 and R 3 , together with the carbon atoms to which they are attached, form a substituted or unsubstituted 3-8 membered ring; R 4 and R 5 are independently hydrogen, halogen or -OR C , where R C is hydrogen or substituted or unsubstituted C1-C6 alkyl, or R 4 and R 5 , together with the carbon atom to which they are attached, form an oxo group; R 6 is absent or is hydrogen; and represents a single bond or a double bond, where When one of them is a double bond, the other is a single bond; when two When both are single bonds, R 6 is hydrogen; and when When one of them is a double bond, R 6 Does not exist.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound is:

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

8. Use of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7, in the preparation of a medicament for treating or preventing a disorder described herein.

9. Use of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7, in the preparation of a medicament for treating or preventing a CNS-related disorder.

10. A method for studying the positive allosteric modulatory activity of a compound on GluN1 / GluN2A and GluN2B glutamate receptors expressed in mammalian cells, comprising: a. HEK293 cells were transformed with adenovirus 5 DNA and transfected with cDNA encoding human GRIN1 / GRIN2A genes; b. using G418 and Zeocin resistance genes incorporated into the expression plasmid to select stable transfectants, and maintaining the selection pressure in the medium with G418 and Zeocin; c. The cells were cultured in Dulbecco's modified Eagle medium / nutrient mixture (D-MEM / F-12) supplemented with 10% fetal bovine serum, 100 μg / ml penicillin G sodium, 100 μg / ml streptomycin sulfate, 100 μg / ml Zeocin, 5 μg / ml blasticidin, and 500 μg / ml G418; d. Evaluate the test article effect in an 8-point concentration-response format (4 pairs of replicate wells / concentration); e. All test and control solutions contained 0.3% DMSO and 0.01% EL (C5135, Sigma); f. The test article formulations were loaded into 384-well compound plates using an automated liquid handling system (SciCloneALH3000, Caliper LifeScienses); g. Measured using the Ion Works Barracuda platform.

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