3α-hydroxy-17β-amide nerve stimulating steroid and its composition

Abstract

To provide 3α-hydroxy-17β-amide neuroactive steroids and compositions thereof.SOLUTION: Provided herein is a compound of the formula (I) in the figure or pharmaceutically acceptable salt thereof, where R2a, R2b, R4a, R4b, R6, R7, R11a, R11b, R16, R17, R3, R5, R19, RX and RY are as defined herein. Also provided herein are pharmaceutical compositions comprising a compound of the formula (I) and methods of using the compounds, e.g., in treatment of CNS-related disorders. Provided herein are compounds designed, for example, to act as GABA modulators. In some embodiments, such compounds are expected to be useful as therapeutic agents for treating a CNS-related disorder.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Application No. 62 / 784,222 (filed December 21, 2018) and U.S. Application No. 62 / 784,229 (filed December 21, 2018) (the entire contents of each are incorporated herein by reference). [Background technology]

[0002] Background of the Invention Brain excitability is defined as the range of animal arousal from coma to convulsions and is controlled by various neurotransmitters. Generally, neurotransmitters are involved in regulating the conductance of ions across the neuronal membrane. At rest, the neuronal membrane has a potential (or membrane voltage) of approximately -70mV, and the inside of the cell is negative relative to the outside. The potential (voltage) is controlled by ions (K) across the neuronal semipermeable membrane. + na + Cl - This is a result of the balance of organic anions. Neurotransmitters are stored in presynaptic vesicles and released under the influence of neuronal action potentials. When released into the synaptic cleft, excitatory chemical neurotransmitters such as acetylcholine cause membrane depolarization (a change in potential from -70mV to -50mV). This action is due to Na + This process is mediated by postsynaptic nicotinic receptors, which are stimulated by acetylcholine, an ion-permeability enhances membrane permeability. The reduced membrane potential stimulates neuronal excitability in the form of postsynaptic action potentials.

[0003] In the case of GABA receptor complexes (GRCs), their effect on brain excitability is mediated by the neurotransmitter gamma-aminobutyric acid (GABA). Since up to 40% of neurons in the brain utilize GABA as a neurotransmitter, GABA has a significant impact on overall brain excitability. GABA regulates the excitability of individual neurons by controlling the conductance of chloride ions across the neuronal membrane. By interacting with recognition sites on GRCs, GABA promotes the flow of chloride ions into the cell downwards along the GRC's electrochemical gradient. This increase in intracellular anion levels causes hyperpolarization of the membrane potential, reducing the neuron's sensitivity to excitatory input (i.e., decreasing neuronal excitability). In other words, the higher the chloride ion concentration within a neuron, the lower the brain's excitability and arousal levels.

[0004] GRCs are well-established to be involved in mediating anxiety, seizure activity, and sedation. Therefore, GABA, and drugs that act like GABA or enhance its effects (e.g., therapeutically beneficial barbiturates and benzodiazepines (BZs), e.g., Valium®), derive their therapeutically beneficial effects by interacting with specific regulatory sites on GRCs. Accumulated evidence now suggests that GRCs contain distinct sites for neurostimulant steroids, in addition to benzodiazepine and barbiturate binding sites. See, for example, Lan, NC et al., Neurochem. Res. (1991) 16:347-356.

[0005] Neurostimulant steroids can be endogenously produced. The most potent endogenous neurostimulant steroids are 3α-hydroxy-5-reduced pregnane-20-one and 3α-21-dihydroxy-5-reduced pregnane-20-one (metabolites of the hormonal steroids progesterone and deoxycorticosterone, respectively). The ability of these steroid metabolites to alter brain excitability was recognized in 1986 (Majewska, MD et al., Science 232:1004-1007 (1986); Harris on, NL et al., J Pharmacol. Exp. Ther. 241:346-353 (1987). Novel and improved compounds that act as modulators of brain excitability, as well as agents for the prevention and treatment of CNS-related disorders, are needed. The compounds, compositions, and methods described herein are intended for this purpose. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Lan, NC et al., Neurochem. Res. (1991) 16:347-356 [Non-Patent Document 2] Majewska, MD et al., Science 232:1004-1007(1986) [Non-Patent Document 3] Harrison, NL et al., J Pharmacol. Exp. Ther. 241:346-353 (1987) [Overview of the project] [Means for solving the problem]

[0007] For example, compounds designed to act as GABA modulators are provided herein. In some embodiments, such compounds are envisioned to be useful as therapeutic agents for treating CNS-related disorders.

[0008] In some embodiments, the formula (I) is provided herein: [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0009] In some embodiments, the formula (IX) is provided herein: [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, the formula (I) is provided herein: [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, the compound of formula (I) is formula (Ia): [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0012] In some embodiments, the compound of formula (I) is formula (I-b1) or formula (I-b2): [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, the compound of formula (I) is formula (I-c1) or formula (I-c2): [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, the compound of formula (I) is formula (I-d1) or formula (I-d2): [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments, the compound of formula (I) is formula (I-d1): [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0016] In some embodiments, the compound of formula (I) is formula (I-d2): [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0017] In some embodiments, the compound of formula (I) is formula (Ie): [ka] A compound of or a pharmaceutically acceptable salt thereof, where R Y is a heteroaryl R 1 It is either -CH2CH3 or -CH3.

[0018] In some embodiments, the compound of formula (I) is formula (If): [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments, the compound of formula (I) is of formula (Ig) [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, the pharmaceutical composition comprises compounds described herein or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients.

[0021] In some embodiments, in subjects requiring treatment for a CNS-related disorder, a method for treating the CNS-related disorder comprises administering to the subject an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the CNS-related disorder is a sleep disorder, mood disorder, schizophrenia spectrum disorder, seizure disorder, memory and / or cognitive impairment, motor disorder, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disorder, substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus. In some embodiments, the CNS-related disorder is depression. In certain embodiments, the CNS-related disorder is postpartum depression. In certain embodiments, the CNS-related disorder is major depressive disorder. In some embodiments, the major depressive disorder is moderate major depressive disorder. In some embodiments, the major depressive disorder is severe major depressive disorder.

[0022] In some embodiments, the compound is selected from the group consisting of the compounds specified in Table 1 herein.

[0023] In one aspect, pharmaceutically acceptable salts of compounds described herein (e.g., compounds of formula (I)) are provided herein.

[0024] In one aspect, a pharmaceutical composition comprising a compound described herein (e.g., a compound of formula (I)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Provided herein. In certain embodiments, the compounds of the present invention are provided in an effective amount in a pharmaceutical composition. In certain embodiments, the compounds of the present invention are provided in a therapeutically effective amount. In certain embodiments, the compound of the present invention is provided in a preventively effective amount.

[0025] The compounds of the present invention described herein, in certain embodiments, are, for example, GABA AIt acts as a GABA modulator that acts on receptors in a positive or negative manner. Such compounds are expected to have CNS activity as regulators of the excitability of the central nervous system (CNS) mediated by their ability to modulate GABA A receptors.

[0026] Thus, in another aspect, there is provided a method of treating a CNS-related disorder in a subject who requires treatment of a CNS-related disorder, the method comprising administering to the subject an effective amount of a compound of the present invention. In certain embodiments, the CNS-related disorder is a sleep disorder, mood disorder, schizophrenia spectrum disorder, seizure disorder, memory and / or cognitive disorder, movement disorder, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disease, substance use disorder and / or withdrawal syndrome, tinnitus, or status epilepticus. In certain embodiments, the CNS-related disorder is depression. In certain embodiments, the CNS-related disorder is postpartum depression. In certain embodiments, the CNS-related disorder is a major depressive disorder. In certain embodiments, the major depressive disorder is a moderate major depressive disorder. In certain embodiments, the major depressive disorder is a severe major depressive disorder. In certain embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered orally. In certain embodiments, the compound is administered for a long term. In certain embodiments, the compound is administered continuously, for example, by continuous intravenous infusion.

[0027] In a preferred embodiment, the compounds described herein selectively modulate a particular subunit composition of the GABA A receptor (e.g., the α4β3δ subunit composition). In embodiments of the present invention, for example, the following items are provided. (Item 1) Formula (I): [Chemical formula] A compound or a pharmaceutically acceptable salt thereof In equation (I), [ka] When the bond valency is permissible, it represents a single or double bond; R 2a , R 2b , R 4a , R 4b , R 6 , R 7 , R 11a , and R 11b Each of these independently consists of hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, -OR D1 -OC(=O)R D1 -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 And here, R in each case D1 R independently consists of hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl, an oxygen protecting group when bonded to an oxygen atom, a nitrogen protecting group when bonded to a nitrogen atom, or two R D1 The groups bond to form substituted or unsubstituted heterocyclic rings; or R 2a and R 2b , R 4a and R 4b , R 7a and R 7b , R 11a and R 11b One of these combines to form an oxo (=O) group; R 16 and R 17Each of these is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2, -N(R A1 ), -CN(R A1 )2, -C(O)R A1 -OC(=O)R A1 , -OC(=O)OR A1 -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 -SC(=O)SR A1 -SC(=O)N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2R A2 -OS(=O)2OR A1 -SS(=O)2R A2 -SS(=O)2OR A1 -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 And here, R in each case A1 These are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group when bonded to an oxygen atom, sulfur protecting group when bonded to a sulfur atom, nitrogen protecting group when bonded to a nitrogen atom, -SO2R A2 , -C(O)R A2 is either or two R A1 They combine to form substituted or unsubstituted heterocyclic rings or heteroaryl rings; RA2 is 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; R 3 is hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; [ka] If both are single bonds, R 5 is hydrogen or methyl; [ka] If one of them is a double bond, R 5 It does not exist; R 19 is hydrogen or a substituted or unsubstituted alkyl group; R X These are independently hydrogen, or substituted or unsubstituted alkyl groups. R Y A compound or a pharmaceutically acceptable salt thereof, which is independently a substituted or unsubstituted heteroaryl compound. (Item 2) The compound of formula (I) is of formula (IX): [ka] It is a compound of, [ka] When the bond valency is permissible, it represents a single or double bond; R 2a , R 2b , R 4a , R 4b , R6 , R 7 , R 11a , and R 11b each independently is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 , where in each case R D1 independently is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when bonded to an oxygen atom, a nitrogen protecting group when bonded to a nitrogen atom, or two R D1 groups are bonded to form a substituted or unsubstituted heterocyclic ring; or R 2a and R 2b , R 4a and R 4b , R 7a and R 7b , R 11a and R 11b any one of them is bonded to form an oxo(=O) group; R 16 and R 17 each independently is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2, -N(R A1 ), -CN(R A1 )2, -C(O)R A1 , -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SRA1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 -SC(=O)SR A1 -SC(=O)N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2R A2 -OS(=O)2OR A1 -SS(=O)2R A2 -SS(=O)2OR A1 -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 And here, R in each case A1 These are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group when bonded to an oxygen atom, sulfur protecting group when bonded to a sulfur atom, nitrogen protecting group when bonded to a nitrogen atom, -SO2R A2 , -C(O)R A2 is either or two R A1 They combine to form substituted or unsubstituted heterocyclic rings or heteroaryl rings; R A2 is 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; R 3 is hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; [ka] If both are single bonds, R 5 is hydrogen or methyl; [ka] If one of them is a double bond, R 5 It does not exist; R 19 is hydrogen or methyl; R X These are independently hydrogen, or substituted or unsubstituted alkyl groups. R Y The compounds described in item 1 or their pharmaceutically acceptable salts, which are independently substituted or unsubstituted heteroaryl compounds. (Item 3) The compound of formula (I) is formula (I-1): [ka] It is a compound of, [ka] When the bond valency is permissible, it represents a single or double bond; R 2a , R 2b , R 4a , R 4b , R 6 , R 7 , R 11a , and R 11b Each of these independently consists of hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, -OR D1 -OC(=O)R D1 -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 And here, R in each case D1R independently consists of hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl, an oxygen protecting group when bonded to an oxygen atom, a nitrogen protecting group when bonded to a nitrogen atom, or two R D1 The groups bond to form substituted or unsubstituted heterocyclic rings; or R 2a and R 2b , R 4a and R 4b , R 7a and R 7b , R 11a and R 11b One of these combines to form an oxo (=O) group; R 16 and R 17 Each of these is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2, -N(R A1 ), -CN(R A1 )2, -C(O)R A1 -OC(=O)R A1 , -OC(=O)OR A1 -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 -SC(=O)SR A1 -SC(=O)N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2R A2 -OS(=O)2OR A1-SS(=O)2R A2 -SS(=O)2OR A1 -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 And here, R in each case A1 These are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted carbocyclyl substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group when bonded to an oxygen atom, sulfur protecting group when bonded to a sulfur atom, nitrogen protecting group when bonded to a nitrogen atom, -SO2R A2 , -C(O)R A2 is either or two R A1 They combine to form substituted or unsubstituted heterocyclic rings or heteroaryl rings; R A2 is 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; R 3 is hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; [ka] If both are single bonds, R 5 It is methyl; [ka] If one of them is a double bond, R 5 It does not exist; R 19 is hydrogen or methyl; R XThese are independently hydrogen, or substituted or unsubstituted alkyl groups. R Y The compounds described in item 1 or 2, or pharmaceutically acceptable salts thereof, are independently substituted or unsubstituted heteroaryl compounds. (Item 4) R 2a and R 2b Each of these independently consists of hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 -OC(=O)R D1 -NH2, or -N(R D1 )2, where R in each case D1 The compounds described in items 1-3, wherein each is independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. (Item 5) R 2a and R 2b A compound according to any one of items 1 to 4, wherein each of the elements is independently hydrogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 haloalkyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C1-C6 alkoxyhalo group, or an -OH group. (Item 6) R 2a and R 2b A compound described in any one of items 1 to 5, wherein is independently hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2. (Item 7) R 2a and R 2b Each of these compounds is independently a hydrogen atom, as described in any one of items 1 to 6. (Item 8) R 2a and R 2b A compound described in any one of items 1-7, in which both atoms are hydrogen. (Item 9) R 4a and R 4bEach of these independently consists of hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 -OC(=O)R D1 -NH2, or -N(R D1 )2, where R in each case D1 These are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclyl A loaryl compound, as described in any one of items 1 to 8. (Item 10) R 4a and R 4b A compound according to any one of items 1 to 9, wherein each of the elements is independently hydrogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 haloalkyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C1-C6 alkoxyhalo group, or an -OH group. (Item 11) R 4a and R 4b A compound described in any one of items 1 to 10, wherein is independently hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2. (Item 12) R 4a and R 4b Each of these compounds is independently a hydrogen atom, as described in any one of items 1 to 11. (Item 13) R 4a and R 4b A compound described in any one of items 1 to 12, wherein both atoms are hydrogen. (Item 14) R 11a and R 11b Each of these independently consists of hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and -OR D1 -OC(=O)R D1 -NH2, or -N(R D1 )2, where R in each case D1A compound according to any one of items 1 to 13, wherein is independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. (Item 15) R 11a and R 11b A compound according to any one of items 1 to 14, wherein each of the elements is independently hydrogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 haloalkyl group, a substituted or unsubstituted C1-C6 alkoxy group, or a substituted or unsubstituted C1-C6 alkoxyhalo group. (Item 16) R 11a and R 11b A compound described in any one of items 1 to 15, wherein is independently hydrogen, -CH3, -CH2CH3, -OCH3, or -CH(CH3)2. (Item 17) R 11a and R 11b Each of these compounds is independently a hydrogen atom, as described in any one of items 1 to 16. (Item 18) R 11a and R 11b A compound described in any one of items 1 through 17, wherein both atoms are hydrogen. (Item 19) R 7 Each of these independently consists of hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 -OC(=O)R D1 -NH2, or -N(R D1 )2, where R in each case D1 A compound according to any one of items 1 to 18, wherein is independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. (Item 20) R 7A compound according to any one of items 1 to 19, wherein each of the elements is independently hydrogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 haloalkyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C1-C6 alkoxyhalo group, or an -OH group. (Item 21) R 7 These are independently hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -C A compound that is H(CH3)2 and is listed in any one of items 1 to 20. (Item 22) R 7 A compound that is hydrogen, as described in any one of items 1 to 20. (Item 23) R 6 These are independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 -OC(=O)R D1 -NH2, or -N(R D1 )2, where R in each case D1 A compound according to any one of items 1 to 22, wherein is independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. (Item 24) R 6 A compound according to any one of items 1 to 23, wherein each of the elements is independently hydrogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 haloalkyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C1-C6 alkoxyhalo group, or an -OH group. (Item 25) R 6 A compound described in any one of items 1 to 24, wherein is independently hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2. (Item 26) R 6 A compound that is hydrogen, as described in any one of items 1 to 25. (Item 27) R 16 Each of these independently consists of hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 -OC(=O)R D1 -NH2, or -N(R D1 )2, where R in each case D1 A compound according to any one of items 1 to 26, wherein is independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. (Item 28) R 16 A compound according to any one of items 1 to 27, wherein each of the elements is independently hydrogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 haloalkyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C1-C6 alkoxyhalo group, or an -OH group. (Item 29) R 16 A compound described in any one of items 1 to 28, wherein is independently hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2. (Item 30) R 16 A compound that is hydrogen, as described in any one of items 1 to 29. (Item 31) R 17 Each of these independently consists of hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 -OC(=O)R D1 -NH2, or -N(R D1 )2, where R in each case D1 A compound according to any one of items 1 to 29, wherein is independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. (Item 32) R 17 A compound according to any one of items 1 to 31, wherein each of the elements is independently hydrogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 haloalkyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C1-C6 alkoxyhalo group, or an -OH group. (Item 33) R 17 A compound described in any one of items 1 to 32, wherein is independently hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2. (Item 34) R 17 A compound that is hydrogen, as described in any one of items 1 to 33. (Item 35) R 19 The compound is independently hydrogen, or a substituted or unsubstituted C1-C6 alkyl group, as described in any one of items 1-34. (Item 36) R 19 The compound is independently hydrogen or a substituted or unsubstituted C1-C4 alkyl group, as described in any one of items 1-35. (Item 37) R 19 A compound described in any one of items 1 to 36, wherein is independently hydrogen, -CH3, -CH2CH3, or -CH2OCH(CH3)2. (Item 38) R 19 A compound that is hydrogen, as described in any one of items 1 to 37. (Item 39) R 19 The compound is -CH2OCH(CH3)2, as described in any one of items 1 to 38. (Item 40) R 3 The compound is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclyl, or a substituted or unsubstituted heterocyclyl, as described in any one of items 1 to 39. (Item 41) R3 The compound is a substituted or unsubstituted alkyl compound as described in any one of items 1 to 40. (Item 42) R 3 The compound is a substituted or unsubstituted C1-C6 alkyl group, as described in any one of items 1-41. (Item 43) The compound of formula (I) is formula (Ia): [ka] A compound of or a pharmaceutically acceptable salt thereof, Here, R 1 The compound is a substituted or unsubstituted alkyl compound as described in any one of items 1 to 42. (Item 44) R 1 is a compound listed in any one of items 1 to 43, which is -CH2CH3 or -CH3. (Item 45) R 1 The compound is -CH2CH3 and is one of the compounds listed in any one of items 1 to 44. (Item 46) R 1 is a compound that is -CH3 and is one of the compounds listed in any one of items 1 to 45. (Item 47) The compound of formula (I) is either formula (I-b1) or formula (I-b2): [ka] A compound described in any one of items 1 to 46, which is a compound of or a pharmaceutically acceptable salt thereof. (Item 48) The compound of formula (I) is formula (I-c1) or formula (I-c2): [ka] A compound described in any one of items 1 to 47, which is a compound of or a pharmaceutically acceptable salt thereof. (Item 49) The compound of formula (I) is of formula (I-d1) or formula (I-d2). [ka] A compound described in any one of items 1 to 48, which is a compound of or a pharmaceutically acceptable salt thereof. (Item 50) The compound of formula (I) is formula (I-d1): [ka] A compound described in any one of items 1 to 49, which is a compound of or a pharmaceutically acceptable salt thereof. (Item 51) The compound of formula (I) is of formula (I-d2): [ka] A compound described in any one of items 1 to 50, which is a compound of or a pharmaceutically acceptable salt thereof. (Item 52) R X These are independently hydrogen, or substituted or unsubstituted C 1~6 A compound that is alkyl, as described in any one of items 1 to 51. (Item 53) R X These are independently hydrogen, or substituted or unsubstituted C 1~4 A compound that is alkyl, as described in any one of items 1 to 52. (Item 54) R X A compound described in any one of items 1 to 53, wherein is independently hydrogen, -CH3, or -CH2CH3. (Item 55) R X A compound that is hydrogen, as described in any one of items 1 to 54. (Item 56) The compound of formula (I) is formula (Ie): [ka] A compound of or a pharmaceutically acceptable salt thereof, where R Y It is a heteroaryl, and R 1 A compound described in any one of items 1 to 55, wherein -CH2CH3 or -CH3. (Item 57) R Y teeth, [ka] Selected from, Here, R in each case D These are independently hydrogen, halogen, -NO2, -CN, -OR GA , -N(R GA )2, -C(=O)R GA , -C(=O)OR GA -C(=O)N(R GA )2, -OC(=O)R GA , -OC(=O)OR GA , -N(R GA )C(=O)R GA , -OC(=O)N(R GA )2, -N(R GA )C(=O)OR GA -S(=O)2R GA -S(=O)2OR GA -OS(=O)2R GA -S(=O)2N(R GA )2, or -N(R GA )S(=O)2R GA , substitution or non-substitution C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, substituted or unsubstituted C 3~4 Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, C 5~10 A substituted or unsubstituted aryl, a substituted or unsubstituted 5- to 10-membered heteroaryl, or two R as needed GAThese atoms combine with intervening atoms to form substituted or unsubstituted 3-4 membered carbocyclic or heterocyclic rings; Here, R in each case GA These are independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, substituted or unsubstituted C 3~6 Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group when bonded to oxygen, nitrogen protecting group when bonded to nitrogen, or two R GA The group combines with an intervening atom to form a substituted or unsubstituted carbocyclic ring or a heterocyclic ring; Here, R in each case X1 is hydrogen, or a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted carbocyclyl. The compound described in any one of items 1 through 56, where e is 0, 1, 2, 3, 4, or 5. (Item 58) R Y teeth, [ka] Selected from, Here, R in each case D These are independently hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, -CN, substituted or unsubstituted 5- to 6-membered heteroaryl, substituted or unsubstituted 5-membered heterocyclyl, The compound described in any one of items 1 through 57, where e is 0, 1, 2, 3, or 4. (Item 59) R Y teeth, [ka] Selected from; Here, R is a compound listed in any one of items 1 to 58, where R is -CH3, -CH2CH3, -i-Pr, cyclopropyl, or -CN. (Item 60) R Y teeth, [ka] A compound selected from any one of items 1 to 59. (Item 61) R Y teeth, [ka] A compound described in any one of items 1 to 60. (Item 62) R Y teeth, [ka] A compound described in any one of items 1 to 61. (Item 63) The aforementioned compound, [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9] [Table 4-10] [Table 4-11] [Table 4-12] [Table 4-13] [Table 4-14] A compound selected from any one of items 1 to 62. (Item 64) The compound of formula (I) is formula (If): [ka] The compounds described in item 1, which are compounds of or pharmaceutically acceptable salts thereof. (Item 65) The compound of formula (I) is of formula (Ig) [ka] The compounds described in item 1, which are compounds of or pharmaceutically acceptable salts thereof. (Item 66) A pharmaceutical composition comprising a compound described in any one of items 1 to 63 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. (Item 67) A method for treating a CNS-related disorder in a subject requiring treatment for a CNS-related disorder, comprising the step of administering to the subject an effective amount of a compound described in any one of items 1 to 65 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in item 66. (Item 68) The method according to item 67, wherein the CNS-related disorder is a sleep disorder, mood disorder, schizophrenia spectrum disorder, seizure disorder, memory and / or cognitive impairment, motor disorder, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disorder, substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus. (Item 69) The aforementioned CNS-related disorder is depression, as described in item 67. (Item 70) The CNS-related disorder is postpartum depression, as described in item 67. (Item 71) The CNS-related disorder is major depressive disorder, as described in item 67. (Item 72) The method described in item 67, wherein the major depressive disorder is a moderate major depressive disorder. (Item 73) The aforementioned major depressive disorder is severe major depressive disorder, as described in item 67. [Modes for carrying out the invention]

[0028] Detailed description of specific embodiments of the invention As generally described herein, the present invention relates to, for example, GABA A The present invention provides a neurostimulant steroid designed to act as a regulatory factor. In preferred embodiments, the compounds described herein are GABA ASelectively modulates a specific subunit composition of the receptor (e.g., α4β3δ subunit composition). As used herein, “selectively modulates” means “GABA”. A This means that a particular subunit composition is modulated to a greater degree or greater extent compared to other subunit compositions of the receptor. In certain embodiments, such compounds are envisioned to be useful as therapeutic agents for treating CNS-related disorders (e.g., depression, such as the disorders described herein, e.g., postpartum depression or major depressive disorder).

[0029] definition chemical definition The definitions of specific functional groups and chemical terms are explained in detail below. Chemical elements are identified according to the periodic table (CAS version, Handbook of Chemistry and Physics, 75th edition, inside cover), and specific functional groups are generally defined as they are described therein. Furthermore, general rules of organic chemistry, as well as specific functional parts and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; and Smith and March, March's Advanced Organic Chemistry. Chemistry, 5th Edition, John Wiley & Sons, Inc., New This is described in York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0030] Isomers (e.g., stereoisomers) can be isolated from the mixture by methods known to those skilled in the art (including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts); or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (edited by ELEliel, Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention further includes the compounds described herein as individual isomers substantially free of other isomers, and / or as mixtures of various isomers.

[0031] As used herein, a pure enantiomerized compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., enantiomer-rich). In other words, an "S" type compound is substantially free of "R" type compounds and is therefore enantiomer-rich of "R" type. The terms "enantiomerically pure" or "pure enantiomer" mean that the compound contains more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight of an enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0032] In the compositions provided herein, enantiomerically pure compounds may be present together with other active or inactive components. For example, a pharmaceutical composition containing an enantiomerically pure R-positional / central / carbon compound may, for example, contain about 90% excipients and about 10% enantiomerically pure R-compounds. In certain embodiments, the enantiomerically pure R-compound in such a composition may, for example, consist of at least about 95% by weight of the R-compound and at most about 5% by weight of the S-compound relative to the total weight of the compound. For example, a pharmaceutical composition containing an enantiomerically pure S-compound may, for example, contain about 90% excipients and about 10% enantiomerically pure S-compounds. In certain embodiments, the enantiomerically pure S-compound in such a composition may, for example, consist of at least about 95% by weight of the S-compound and at most about 5% by weight of the R-compound relative to the total weight of the compound. In certain embodiments, the active ingredient may be formulated with small amounts of excipients or carriers, or without excipients or carriers.

[0033] The term "diastereomerically pure" means that the compound is present in amounts exceeding 75% by weight, 80% by weight, 85% by weight, 90% by weight, 91% by weight, 92% by weight, 93% by weight, 94% by weight, 95% by weight, 96% by weight, 97% by weight, 98% by weight, 98.5% by weight, 99% by weight, 99.2% by weight, 99.5% by weight, and 99.6% by weight. This means that the compound contains more than 99.7% by weight, more than 99.8% by weight, or more than 99.9% by weight of a single diastereomer. Methods for determining diastereomer purity and enantiomer purity are well known in the art. Diastereomer purity can be determined by any analytical method (such as high-performance liquid chromatography (HPLC)) that can quantitatively distinguish between the compound and its diastereomer.

[0034] "Stereoisomers": It should be understood that compounds having the same molecular formula but differing in atomic properties, bond order, or spatial arrangement of atoms are also called "isomers." Isomers that differ in spatial arrangement of atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and those that are mirror images that cannot be superimposed on each other are called "enantiomers." For example, if a compound has a chiral center, it is bonded to four different groups, and a set of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and expressed by the Kahn-Prelogue R and S ordering rules, or by the way the molecule rotates its plane of polarization, and are dextrorotatory or levorotatory (i.e., (+) or (-)-isomers, respectively). Chiral compounds can exist either as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0035] The articles "a" and "an" may be used herein to indicate that the grammatical object of the article is one or more (i.e., at least one). For example, "an analogue" means one analog or more analogs.

[0036] When a range of values ​​is enumerated, it is intended to include each value and subrange within that range. For example, "C 1~6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 , and C 5~6 It is intended to include alkyl groups.

[0037] The following terms are intended to have the meanings presented below and are useful in understanding the scope intended in this specification and the invention.

[0038] "Alkyl" refers to a radical of a linear or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C"). 1~20 This refers to an alkyl group having 1 to 12 carbon atoms. In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C"). 1~12 Alkyl). In some embodiments, the alkyl group has 1 to 10 carbon atoms ("C"). 1~10 Alkyl). In some embodiments, the alkyl group has 1 to 9 carbon atoms (C). 1~9 ("alkyl"). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C"). 1~8 Alkyl). In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C"). 1~7 "Alkyl") In some embodiments, the alkyl group has 1 to 6 carbon atoms (also referred to herein as "lower alkyl" or "C"). 1~6 ("alkyl"). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C"). 1~5 (alkyl). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C"). 1~4 (alkyl). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C"). 1~3 Alkyl). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C"). 1~2 Alkyl). In some embodiments, the alkyl group has one carbon atom ("C1 alkyl"). In some embodiments, the alkyl group has two to six carbon atoms ("C1 alkyl"). 2~6 Alkyl). C 1~6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), and iso Examples of alkyl groups include propyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and others. Unless otherwise specified, each alkyl group may be independently substituted as needed, i.e., unsubstituted ("unsubstituted alkyl") or with one or more substituents; for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, the alkyl group is unsubstituted C 1~10 It is an alkyl group (e.g., -CH3). In certain embodiments, the alkyl group is a substituted C 1~10 It is an alkyl group. Common abbreviations for alkyl groups include Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2).

[0039] "Alkylene" refers to an alkyl group from which two hydrogen atoms have been removed to form a divalent radical, and can be substituted or unsubstituted. Examples of unsubstituted alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), and hexylene (-CH2CH2CH2CH2CH2CH2-). Examples of substituted alkylene groups, for example, 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 -CH2CH2C(CH3)2-). When a range or number of carbon atoms is given to a particular alkylene group, the aforementioned range or number is understood to refer to a range or number of carbon atoms in a divalent carbon linear chain. The alkylene group may be substituted with one or more substituents described herein or unsubstituted.

[0040] "Alkenyl" refers to a radical of a linear or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 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 This refers to an alkenyl group. In certain embodiments, the alkenyl group does not contain any triple bond. In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C"). 2~10 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C"). 2~9("Alkenyl"). In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C"). 2~8 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C"). 2~7 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C"). 2~6 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C"). 2~5 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C"). 2~4 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C"). 2~3 "Alkenyl"). In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). One or more carbon-carbon double bonds may be located internally (e.g., 2-butenyl) or at the terminal (e.g., 1-butenyl). C 2~4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl ( Examples include C4, butadienyl (C4), etc. 2~6 An example of an alkenyl group is the aforementioned C 2~4 Examples of alkenyl groups include pentenyl (C5), pentadienyl (C5), and hexenyl (C6). Further examples of alkenyls include heptenyl (C7), octenyl (C8), and octatrienyl (C8). Unless otherwise specified, each presence of an alkenyl group can be independently substituted as needed, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, the alkenyl group is an unsubstituted C 2~10 It is an alkenyl. In certain embodiments, the alkenyl group is a substituted C 2~10 It is Alkenil.

[0041] "Alkynnyl" refers to a radical of a linear or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 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 This refers to an "alkynyl" group. In certain 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 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 9 carbon atoms ("C"). 2~9 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C"). 2~8 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 7 carbon atoms ("C"). 2~7 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C"). 2~6 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C"). 2~5 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C"). 2~4 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C"). 2~3 "Alkynyl"). In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). One or more carbon-carbon triple bonds may be located internally (e.g., 2-butynyl) or at the terminal (e.g., 1-butynyl). C 2~4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), and 2-butynyl (C4). 2~6 An example of an alkenyl group is the aforementioned C 2~4Examples include alkynyl groups, as well as pentynyl (C5), hexynyl (C6), and the like. Further examples of alkynyls include heptynyl (C7), octinyl (C8), and the like. Unless otherwise specified, each presence of an alkynyl group is independently substituted as needed, i.e., unsubstituted ("unsubstituted alkynyl") or with one or more substituents; for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkynyl"). In certain embodiments, the alkynyl group is an unsubstituted C 2~10 It is an alkynyl group. In certain embodiments, the alkynyl group is a substituted C 2~10 It is alkinyl.

[0042] The term “heteroalkyl” as used herein means an alkyl group as defined herein, further comprising 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 aforementioned one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain, and / or one or more heteroatoms are inserted between carbon atoms and the parent molecule (i.e., between bonding sites). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC"). 1~10 This refers to an alkyl group. In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (hetero C 1~9 It is alkyl). In some embodiments, it is hetero Alkyl groups are saturated groups having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms ("hetero C"). 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 ("hetero C"). 1~7 A heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ("hetero C"). In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ("hetero C").1~6 A heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("hetero C"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("hetero C"). 1~5 A heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms ("hetero C"). In some embodiments, the heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms ("hetero C"). 1~4 A heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom ("hetero C"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom ("hetero C"). 1~3 A heteroalkyl group is a saturated group having 1-2 carbon atoms and 1 heteroatom ("hetero C"). In some embodiments, a heteroalkyl group is a saturated group having 1-2 carbon atoms and 1 heteroatom ("hetero C"). 1~2 In some embodiments, the heteroalkyl group is a saturated group having one carbon atom and one heteroatom ("heteroC1 alkyl"). In some embodiments, the heteroalkyl group is a saturated group having two to six carbon atoms and one or two heteroatoms ("heteroC1 alkyl"). 2~6 The heteroalkyl group is an alkyl group. Unless otherwise specified, each heteroalkyl group is independently either unsubstituted ("unsubstituted heteroalkyl group") or substituted with one or more substituents ("substituted heteroalkyl group"). In certain embodiments, the heteroalkyl group is an unsubstituted heteroalkyl group. 1~10 It is alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC 1~10 It is alkyl.

[0043] "Aryl" refers to a radical ("C") of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) in which 6 to 14 ring carbon atoms and 0 heteroatoms are provided to the aromatic ring system. 6~14 This refers to an aryl group. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10"Aryl"; for example, naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C"). 14 "Aryl" (e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused with one or more carbocyrillic or heterocyclyl groups, where the bonding radical or bond site is located on the aryl ring, and in such cases the number of carbon atoms still indicates the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, those derived from acetantrylene, acetanaphthylene, acetphenantrylene, anthracene, azulene, benzene, chrysene, coronene, fluorantene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indan, indene, naphthalene, octacene, octafen, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiaden, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. In particular, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each presence of an aryl group is independently substituted as necessary, i.e., either unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, the aryl group is an unsubstituted C 6~14 It is aryl. In certain embodiments, the aryl group is substituted C 6~14 It is Ariel.

[0044] In certain embodiments, the aryl group is substituted with one or more groups selected from halo, C1-C8 alkyl, C1-C8 haloalkyl, cyano, hydroxy, C1-C8 alkoxy, and amino.

[0045] Typical examples of substitution aryls include the following: [ka] Here, R 56 and R 57 One of them can be hydrogen, and R 56 and R 57 At least one of them is independently a C1-C8 alkyl, C1-C8 haloalkyl, 4-10 member heterocyclyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, or NR. 58 COR 59 , NR 58 SOR 59 , NR 58 SO2R 59 COOalkyl, COOaryl, CONR 58 R 59 CONR 58 Ure 59 , NR 58 R 59 SO2NR 58 R 59 Selected from S-alkyl, SOalkyl, SO2alkyl, S-aryl, SOaryl, SO2aryl; or R 56 and R 57 These can be linked together to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms (including, as necessary, one or more heteroatoms selected from the group N, O, or S). 60 and R 61 These are independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, and C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl substitution C6~C 10 These are aryl, 5-10 member heteroaryl, or substituted 5-10 member heteroaryl.

[0046] A "condensed aryl" refers to an aryl ring in which two of its ring carbons are shared with a second aryl ring, heteroaryl ring, carbocykyl ring, or heterocyclyl ring.

[0047] "Heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10π electrons shared in the cyclic arrangement) in which a ring carbon atom and 1-4 ring heteroatoms are provided to the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the bond site can be a carbon or nitrogen atom, wherever the bond valency allows. A heteroaryl bicyclic ring system may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused with one or more carbocykryl or heterocyclyl groups, where the bond site is located on the heteroaryl ring, and in such cases the number of ring members still refers to the number of ring members in the heteroaryl ring system. "Hyperaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more aryl groups, where the bond site is located on the aryl ring or the heteroaryl ring, and in such cases, the number of ring members indicates the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups where one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the bond site may be located on either ring, i.e., on the ring with a heteroatom (e.g., 2-indolyl) or on the ring without a heteroatom (e.g., 5-indolyl).

[0048] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system in which a ring carbon atom and 1-4 ring heteroatoms are provided to the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system in which a ring carbon atom and 1-4 ring heteroatoms are provided to the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments In form, a heteroaryl group is a 5-6 membered aromatic ring system in which a ring carbon atom and 1-4 ring heteroatoms are provided to an aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, a 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each presence of a heteroaryl group is independently substituted as necessary, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, a heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, a heteroaryl group is a substituted 5-14 membered heteroaryl.

[0049] Examples of five-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Examples of five-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Examples of five-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Examples of five-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Examples of six-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Examples of six-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Examples of six-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetradinyl, respectively. Examples of seven-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Examples of 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranil, benzoisofuranil, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolidinyl, and prinyl. Examples of 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthylidinyl, pteridinyl, quinolinil, isoquinolinil, sinnolinil, quinoxalinil, phthalazinyl, and quinazolinil.

[0050] Typical examples of heteroaryls include: [ka] These are listed, where each Z is carbonyl, N, NR65 Selected from O and S; R 65 These are independently hydrogen, C1-C8 alkyl, and C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 They are aryl and 5- to 10-membered heteroaryls.

[0051] A "carbocyclyl" or "carbocyclic" structure is a non-aromatic ring system with 3 to 10 ring carbon atoms ("C"). 3~10 This refers to a radical of a non-aromatic cyclic hydrocarbon group having 0 heteroatoms ("carbocyclyl"). In some embodiments, the carbocyclyl group has 3 to 8 ring carbon atoms ("C"). 3~8 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C"). 3~6 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C"). 3~6 Carbocyclyl). In some embodiments, the carbocyclyl group has 5 to 10 ring carbon atoms ("C"). 5~10 Carbocyclyl). Exemplary C 3~6 Examples of carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). 3~8 As for the carbocyclyl group, the above C 3~6 Examples include, but are not limited to, carbocyclyl groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), and bicyclo[2.2.2]octanyl (C8). 3~10 As for the carbocyclyl group, the above C 3~8 Carbocyclyl group, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C9) 10 ), spiro[4.5]decanil(C 10 Examples include, but are not limited to, the above. When the above examples are illustrated, in certain embodiments the carbocyclyl group may be monocyclic ("monocyclic carbocyclyl") or include fused, bridging, or spirocyclic systems (e.g., bicyclic systems ("bicyclic carbocyclyl")) and may be saturated or partially unsaturated. "Carbocyclyl" also includes cyclic systems in which a carbocyclyl ring as defined above is fused with one or more aryl or heteroaryl groups, where the bond site is on the carbocyclyl ring, and in such cases the number of carbons still refers to the number of carbons in the carbocyclic system. Unless otherwise specified, each presence of a carbocyclyl group may be independently substituted as needed, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments the carbocyclyl group may be unsubstituted C 3~ 10 It is a carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C 3~10 It is carbocyclyl.

[0052] In some embodiments, "carbocykrill" is a monocyclic saturated carbocykrill group having 3 to 10 ring carbon atoms ("C 3~10 It is a cycloalkyl group. In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C"). 3~8 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C"). 3~6 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 6 ring carbon atoms ("C"). 5~6 ("Cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 10 ring carbon atoms ("C"). 5~10 Cycloalkyl). C 5~6Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3~6 Examples of cycloalkyl groups include the above C 5~6 Examples include cycloalkyl groups, as well as cyclopropyl (C3) and cyclobutyl (C4). 3~8 Examples of cycloalkyl groups include the above C 3~6 Examples include cycloalkyl groups, as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each cycloalkyl group is independently either unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, the cycloalkyl group is unsubstituted C 3~10 It is a cycloalkyl group. In certain embodiments, the cycloalkyl group is a substituted C 3~10 It is a cycloalkyl group.

[0053] A "heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In a heterocyclyl group containing one or more nitrogen atoms, the bond site can be a carbon or nitrogen atom, where the valence allows. A heterocyclyl group can be a monocyclic ring system ("monocyclic heterocyclyl"), a fused ring system, a bridging ring system, or a spiro-ring system (e.g., a bicyclic ring system ("bicyclic heterocyclyl")), and can be saturated or partially unsaturated. A heterocyclyl bicyclic ring system may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused with one or more carbocyclyl groups, where the bond site is located on the carbocyclyl or heterocyclyl ring, or on ring systems in which a heterocyclyl ring as defined above is fused with one or more aryl or heteroaryl groups, where the bond site is located on the heterocyclyl ring, in which case the number of ring members still refers to the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each presence of heterocyclyl is independently substituted as necessary, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0054] In some embodiments, the heterocyclyl group is a 5-10 membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where 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 a ring carbon atom and 1-4 ring heteroatoms, where 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 a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered hetero A cyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0055] Examples of three-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxyranil, and thiorenyl. Examples of four-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanil, and thietanil. Examples of five-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranil, dihydrofuranil, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Examples of five-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanil, oxasulfuranil, disulfuranil, and oxazolidine-2-one. Examples of five-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Examples of six-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranil, dihydropyridinyl, and thianil. Examples of six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinil, dithianil, and dioxanil. Examples of six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanil. Examples of seven-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanil, oxepanil, and thiepanil. Examples of eight-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azokanil, oxekanil, and thiokanil. Examples of five-membered heterocyclyl groups condensed to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic rings) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranil, dihydrobenzothienyl, and benzoxazolinonil.Examples of six-membered heterocyclyl groups condensed to an aryl ring (also referred to herein as 6,6-bicyclic heterocyclic rings) include, but are not limited to, tetrahydroquinolinyl and tetrahydroisoquinolinyl.

[0056] The term "nitrogen-containing heterocyclyl" refers to a 4- to 7-membered non-aromatic cyclic group containing at least one nitrogen atom (e.g., morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazine (such as N-methylpiperazine)). Specific examples include azetidine, piperidone, and piperazone.

[0057] 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 heteroatoms of nitrogen, oxygen, or sulfur. Hetero can be applied to any of the hydrocarbyl groups described above (alkyls having 1 to 5 heteroatoms, especially 1 to 3, e.g., heteroalkyls, cycloalkyls, e.g., heterocyclyls, aryls, e.g., heteroaryls, and cycloalkenyls, e.g., cycloheteralkenyls).

[0058] "Ashil" is -C(O)R 20 It refers to a radical, and here, R 20 This includes hydrogen, substituted or unsubstituted alkyls, substituted or unsubstituted alkenyls, substituted or unsubstituted alkynyls, substituted or unsubstituted carbocyclyls, and substituted or The terms are unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. "Alkanoyl" is R 20The group other than hydrogen is the acyl group. Representative acyl groups include formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), --C(O)-C1-C8 alkyl, and -C(O)-(CH2). t (C6-C 10 aryl), -C(O)-(CH2) t (5-10 member heteroaryl), -C(O)-(CH2) t (C3-C 10 Cycloalkyl) and -C(O)-(CH2) t Examples include, but are not limited to, (4- to 10-membered heterocyclines) (where t is an integer from 0 to 4). In a particular embodiment, R 21 C1-C8 alkyl groups substituted with halo or hydroxyl; or C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 These are aryl, arylalkyl, 5-10 membered heteroaryl, or heteroarylalkyl (each of which is substituted with an unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy).

[0059] "alkoxy" means -OR 29 It refers to the base, and here, R 29 These are substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted carbocyclyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heteroaryl groups. Certain alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Certain alkoxy groups are lower alkoxy groups, i.e., having 1 to 6 carbon atoms. Further specific alkoxy groups have 1 to 4 carbon atoms.

[0060] In a particular embodiment, R 29 is amino, substituted amino, C6~C 10 Aryl, aryloxy, carboxyl, cyano, C3~C 10 One or more substituents selected from the group consisting of cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2-, and aryl-S(O)2-, for example, a group having 1-5 substituents, in particular 1-3 substituents, in particular 1 substituent. An example of a "substituted alkoxy" group is -O-(CH2) t (C6~C 10 aryl), -O-(CH2) t (5-10 member heteroaryl), -O-(CH2) t (C3~C 10 Cycloalkyl) and -O-(CH2) t Examples include, but are not limited to, 4- to 10-membered heterocyclyl groups, where t is an integer from 0 to 4, and any existing aryl, heteroaryl, cycloalkyl, or heterocyclyl group may itself be substituted with an unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. Particularly exemplary "substituted alkoxy" groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2.

[0061] "Amino" refers to the -NH2 radical.

[0062] The "oxo" group refers to -C(=O)-.

[0063] "Substituting amino acid" refers to the compound of the formula -N(R 38 ) refers to the amino group of 2, where R 38This includes hydrogen, substituted or unsubstituted alkyls, substituted or unsubstituted alkenyls, substituted or unsubstituted alkynyls, substituted or unsubstituted carbocyclyls, substituted or unsubstituted heterocyclyls, substituted or unsubstituted aryls, substituted or unsubstituted heteroaryls, or aminoprotected elements. It is a base, and here, R 38 At least one of them is not hydrogen. In a particular embodiment, each R 38 These are independently hydrogen, C1-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, and C6-C 10 Aryl, 5-10 member heteroaryl, 4-10 member heterocyclyl, or C3-C 10 Cycloalkyl; or C1-C8 alkyl substituted with halo or hydroxyl; C3-C8 alkenyl substituted with halo or hydroxyl; C3-C8 alkynyl substituted with halo or hydroxyl, or -(CH2) t (C6~C 10 Aryl), -(CH2) t (5-10 member heteroaryl), -(CH2) t (C3~C 10 Cycloalkyl) or -(CH2) t Selected from (4-10 member heterocyclyls), where t is an integer from 0 to 8, each of which is substituted with an unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy; or both R 38 The groups bond together to form an alkylene group.

[0064] Examples of "substituted amino" groups include -NR 39 -C1~C8 alkyl, -NR 39 -(CH2) t (C6~C 10 Ariel), -NR 39 -(CH2) t (5-10 member heteroaryl), -NR 39 -(CH2) t (C3~C 10Cycloalkyl) and -NR 39 -(CH2) t Examples include (4-10 member heterocyclyls), but are not limited to these, where t is an integer from 0 to 4, for example, 1 or 2, and each R 39 The group independently represents hydrogen or a C1-C8 alkyl group; any alkyl group present may be substituted by itself a halo, substituted or unsubstituted amino or hydroxyl group; any aryl, heteroaryl, cycloalkyl or heterocyclyl group present may be substituted by itself an unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxyl group. To avoid misunderstanding, the term “substituted amino” includes alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino and substituted dialkylamino groups, as defined below. Substituted aminos include both monosubstituted and disubstituted amino groups.

[0065] "Carboxylate" refers to the -C(O)OH radical.

[0066] "Cyano" refers to the -CN radical.

[0067] "Halo" or "halogen" refers to fluoro(F), chloro(Cl), bromo(Br), and iodine(I). In certain embodiments, the halo group is either fluoro or chloro.

[0068] A "haloalkyl" refers to an alkyl radical in which one or more halogen atoms are substituted for an alkyl group. Typical haloalkyls include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, and tetrafluoroethyl.

[0069] "Hydroxy" refers to the -OH radical.

[0070] "Nitro" refers to the -NO2 radical.

[0071] "Thioketo" refers to the S group.

[0072] Alkyl, alkenyl, alkynyl, carbocyrill, heterocyclyl, aryl, and heteroaryl groups as defined herein may be substituted as necessary (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyrill, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl groups). In general, the term "substituted" means, whether or not preceded by the term "as necessary," that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that, when substituted, produces a stable compound, e.g., a compound that does not undergo spontaneous transformation (e.g., rearrangement, cyclization, elimination, or other reactions). Unless otherwise indicated, a “substituted” group has substituents at one or more substituted positions on that group, and when two or more positions in any given structure are substituted, those substituents are either the same or different at each position. The term “substituted” is intended to include all acceptable substituents of an organic compound, substitution by any substituents described herein that form a stable compound. The present invention intends any and all such combinations to arrive at a stable compound. For the purposes of the present invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any preferred substituents, as described herein, that satisfy the bond valence of the heteroatom and consequently form a stable moiety.

[0073] Examples of carbon atom substituents include halogens, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, and -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb -SH, -SR aa , -SSR cc -C(=O)R aa -CO2H, -CHO, -C(OR cc )2, -CO2R aa -OC(=O)R aa , -OCO2R aa -C(=O)N(R bb )2, -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -C(=NR bb )R aa -C(=NR bb )OR aa -OC(=NR bb )R aa -OC(=NR bb )OR aa -C(=NR bb )N(R bb )2, -OC(=NR bb )N(R bb )2, -NR bb C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa , -NR bb SO2R aa , -SO2N(R bb )2, -SO2R aa , -SO2OR aa , -OSO2R aa -S(=O)R aa -OS(=O)R aa , -Si(R aa)3, -OSi(R aa )3-C(=S)N(R bb )2, -C(=O)SR aa -C(=S)SR aa -SC(=S)SR aa -SC(=O)SR aa -OC(=O)SR aa , -SC(=O)OR aa -SC(=O)R aa -P(=O)2R aa -OP(=O)2R aa -P(=O)(R aa )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenil, C 2~10 Alkinyl, C 3~10 Carbocyclyl, 3-14 member heterocyclyl, C 6~14 Examples include, but are not limited to, aryl and 5- to 14-membered heteroaryl groups, where each alkyl, alkenyl, alkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted by a group; or two geminal hydrogens on a carbon atom, group =O, =S, =NN(R bb )2, =NNR bbC(=O)R aa ,=NNR bb C(=O)OR aa ,=NNR bb S(=O)2R aa ,=NR bb , or =NOR cc Replaced by;

[0074] R aa Each of these beings is independent of C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~ 10 Alkenil, C 2~10 Alkinyl, C 3~10 Carbocyclyl, 3-14 member heterocyclyl, C 6~14 Selected from aryls and 5-14 member heteroaryls, or two R aa The groups are linked to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the base;

[0075] R bb Each of these entities exists independently as hydrogen, -OH, and -OR. aa , -N(R cc )2, -CN, -C(=O)R aa -C(=O)N(R cc )2, -CO2R aa , -SO2R aa -C(=NR cc )OR aa -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc -SOR aa -C(=S)N(R cc )2, -C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(Raa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenil, C 2~10 Alkinyl, C 3~10 Carbocyclyl, 3-14 member heterocyclyl, C 6~14 Selected from aryls and 5-14 member heteroaryls, or two R bb The groups are linked to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the base;

[0076] R cc Each of these entities independently contains hydrogen and C. 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenil, C 2~10 Alkinyl, C 3~10 Carbocyclyl, 3-14 member heterocyclyl, C 6~14 Selected from aryls and 5-14 member heteroaryls, or two R cc The groups are linked to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the base;

[0077] R dd Each of these entities is independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff-SH, -SR ee , -SSR ee -C(=O)R ee -CO2H, -CO2R ee -OC(=O)R ee , -OCO2R ee -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff )OR ee -OC(=NR ff )R ee -OC(=NR ff )OR ee -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee -C(=S)SR ee -SC(=S)SR ee -P(=O)2R ee -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~10Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 Selected from aryls and 5-10 membered heteroaryls, where each alkyl, alkenyl, alkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg Substituted by the base; or two geminal R dd Substituents can combine to form =O or =S;

[0078] R ee Each of these beings is independent of C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~10 Carbocyclyl, C 6~10 Ariel, 3~ Selected from 10-membered heterocyclyls and 3-10-membered heteroaryls, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg Substituted with the base;

[0079] R ff Each of these entities independently contains hydrogen and C. 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 Selected from aryls and 5-10 member heteroaryls, or two R ff The groups are linked to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. gg Substituted with the base;

[0080] R ggEach of these entities 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 1~6Alkyl), -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 1~6 Alkyl)2, C(=S)NH(C 1~6 Alkyl), C(=S)NH2, -C(=O)S(C 1~6 Alkyl), -C(=S)SC 1~6 Alkyl, -SC(=S)SC 1~6 Alkyl, -P(=O)2(C 1~6 Alkyl), -P(=O)(C 1~6 Alkyl)2, -OP(=O)(C 1~6 Alkyl)2, -OP(=O)(OC 1~6 Alkyl)2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~10 Carbocyclyl, C 6~10 It is either an aryl, a 3-10 member heterocyclyl, a 5-10 member heteroaryl; or two geminal Rs. gg Substituents can come together to form =O or =S; where X - It is a counterion.

[0081] A "counterion" or "anionic counterion" is a negatively charged group that associates with a cationic quaternary amino group to maintain electrical neutrality. Examples of counterions include halide ions (e.g., F - Cl - , Br - , I - ), NO3 -ClO4 - , OH - H2PO4 - HSO4 - , sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.) and carboxylate ions (e.g., acetate, ethanolate, propanoate, benzoate) Examples include glycerates, lactates, tartarates, and glycolates.

[0082] These and other exemplary substituents are described in detail in the detailed description and claims. The present invention is not intended to be limited in any way by the exemplary enumeration of substituents described above.

[0083] Other definitions As used herein, the term “modification” means GABA A This refers to the inhibition or synergistic effect of receptor function. A "regulatory factor" (e.g., a regulatory compound) is, for example, GABA. A It can be a receptor agonist, partial agonist, antagonist, or partial antagonist.

[0084] "Pharmacologically acceptable" means that it is approved or can be approved by a federal or state regulatory authority or a corresponding authority in a country other than the United States, or that it is listed in the United States Pharmacopeia or other generally accepted pharmacopoeias for use in animals (more specifically, humans).

[0085] "Pharmacologically acceptable salt" refers to a salt of the compound of the present invention that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. In particular, such salts are nontoxic and may be inorganic acid addition salts or organic acid addition salts and inorganic base addition salts or organic base addition salts. Specifically, such salts include (1) formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or with organic acids, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphor Examples of acid addition salts formed with (2) an acid proton present in the parent compound is a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion; or a salt formed when the compound coordinates with an organic base, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine. Further examples of salts include sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.; and, if the compound contains a basic functional group, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, or oxalate. The term "pharmaceutically acceptable cation" refers to a cationic counterion that can accept an acidic functional group. Examples of such cations include sodium cations, potassium cations, calcium cations, magnesium cations, ammonium cations, and tetraalkylammonium cations.For example, see Berge et al., J.Pharm.Sci.(1977)66(1):1-79.

[0086] The term "prodrug" is intended to include therapeutically inactive compounds that are converted into therapeutically active agents of the present invention under physiological conditions. One method for producing a prodrug involves hydrolysis or cleavage at a targeted in vivo site of action under physiological conditions so that a desired molecule is revealed, and then designing a selective portion that produces its therapeutic effect. In certain embodiments, the prodrug is converted by the enzymatic activity of the subject.

[0087] In an alternative embodiment, the present invention provides a prodrug of a compound of formula (I), the prodrug comprising a cleavable portion on the C3 hydroxyl group as shown in formula (I).

[0088] A "tautomer" is a compound whose specific compound structure is interchangeable, and whose displacement of hydrogen atoms and electrons varies. Thus, the two structures can be in equilibrium through the movement of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either an acid or a base. Another example of tautomerism is the acidic and nitro forms of phenylnitromethane, which are similarly formed by treatment with either an acid or a base. Tautomerism can be relevant to achieving optimal chemical reactivity and biological activity of a compound of interest.

[0089] The “subjects” to which the administration is intended include, but are not limited to, human (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, e.g., mammals (e.g., primates (e.g., cynomolgus macaques, rhesus macaques), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs). In certain embodiments, the subject is human. In certain embodiments, the subject is a non-human animal.

[0090] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also called a hydroxyl protecting group). Examples of oxygen protecting groups include -R aa , -N(R bb )2, -C(=O)SR aa -C(=O)R aa , -CO2R aa -C(=O)N(R bb )2, -C(=NR bb )R aa -C(=NR bb )OR aa -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3, -P(=O)2R aa -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)2N(R bb )2, and -P(=O)(NR bb )2(R here aa , R bb , and R cc Examples include, but are not limited to, oxygen protecting groups (as defined herein). Oxygen protecting groups are well known in the art, such as Protecting Groups in Organic Synthesis, TWGreene and PGMWuts, 3 rd Examples include those described in detail in edition, John Wiley & Sons, 1999 (as incorporated herein by reference).

[0091] Examples of oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), benzyl (Bn), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS), t-butylmethoxyphenylsilyl (TBMPS), methanesulfonate (mesylate), and tosylate (Ts).

[0092] In certain embodiments, substituents on the sulfur atom are sulfur protecting groups (also called thiol protecting groups). Examples of sulfur protecting groups include -R aa , -N(R bb )2, -C(=O)SR aa -C(=O)R aa , -CO2R aa -C(=O)N(R bb )2, -C(=NR bb )R aa -C(=NR bb )OR aa -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3, -P(=O)2R aa -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)2N(R bb )2, and -P(=O)(NR bb )2 is one example, but it is not limited to these, and here R aa , R bb , and R cc This is as defined herein. Sulfur protecting groups are well known in the art, and Protecting Groups in Organic Synthesis,TW Greene and PGMWuts,3 rdExamples include those described in detail in edition, John Wiley & Sons, 1999 (as incorporated herein by reference).

[0093] In certain embodiments, the substituent present on the nitrogen atom is an amino protecting group (also referred to herein as a nitrogen protecting group). Examples of amino protecting groups include -OH and -OR. aa , -N(R cc )2, -C(=O)R aa , -C(=O)OR aa -C(=O)N(R cc )2, -S(=O)2R aa -C(=NR cc )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 , C 1~10 Alkyl, C 2~10 Alkenil, C 2~10 Alkinyl, C 3~10 Carbocyclyl, 3-14 member heterocyclyl, C 6~14 Examples include, but are not limited to, aryl and 5- to 14-membered heteroaryl groups, where each alkyl, alkenyl, alkynyl, carbocykrill, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd It is substituted with the base, where R aa , R bb , R cc , and R dd The amino protecting group is as defined herein. The amino protecting group is well known in the art, as seen in Protecting Groups in Organic Synthesis, TWGreene and PGMWuts, 3 rdExamples include those described in detail in edition, John Wiley & Sons, 1999 (as incorporated herein by reference).

[0094] An example of an amino protecting group is the amide group (e.g., -C(=O)R aa )(Examples include, but are not limited to, formamides and acetamides); carbamate groups (e.g., -C(=O)OR aa )(Examples include, but are not limited to, 9-fluorenylmethylcarbamate (Fmoc), t-butylcarbamate (BOC), and benzylcarbamate (Cbz); sulfonamide group (e.g., -S(=O)2R) aa Examples include, but are not limited to, p-toluenesulfonamide (Ts), methanesulfonamide (Ms), and N-[2-(trimethylsilyl)ethoxy]methylamine (SEM). Diseases, disorders, and conditions are used interchangeably in this specification.

[0095] As used herein, unless otherwise specified, the terms “treat,” “treating,” and “treatment” refer to actions (therapeutic actions) performed while a subject is suffering from a particular disease, disorder, or condition that reduce the severity of the disease, disorder, or condition, or that delay or slow the progression of the disease, disorder, or condition, as well as actions that occur before a subject begins to suffer from a particular disease, disorder, or condition.

[0096] Generally, the “effective dose” of a compound refers to an amount sufficient to elicit a desired biological response, for example, to treat a CNS-related disorder, or to induce anesthesia or sedation. As will be understood by those skilled in the art, the effective dose of the compound of the present invention may vary depending on factors such as the desired biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health status, and condition of the subject.

[0097] Where used herein, unless otherwise specified, “therapeutic dose” of a compound means an amount sufficient to provide therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with that disease, disorder, or condition. “Therapeutic dose” of a compound means the amount of the therapeutic agent, alone or in combination with other treatments, that provides therapeutic benefit in the treatment of that disease, disorder, or condition. The term “therapeutic dose” means the amount that improves the overall treatment, the symptoms of the disease or condition, or This may include amounts that reduce or avoid the cause, or amounts that enhance the therapeutic effect of another therapeutic agent.

[0098] In alternative embodiments, the present invention intends to administer the compound of the present invention or a pharmaceutically acceptable salt or pharmaceutically acceptable composition thereof as a prophylactic agent before a subject begins to develop a particular disease, disorder, or condition. Where used herein, unless otherwise specified, “prophylactic effective dose” of a compound means an amount sufficient to prevent or prevent the recurrence of a disease, disorder, or condition, or one or more symptoms associated with that disease, disorder, or condition. The prophylactic effective dose of a compound means the amount of the therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of the disease, disorder, or condition. The term “prophylactic effective dose” may include an amount that improves the overall prevention or enhances the prophylactic efficacy of another prophylactic agent.

[0099] As used herein, “episodic dosing regimen” is a dosing regimen in which a compound of formula (I) or a composition comprising a compound of formula (I) is administered to a subject over a limited period of time in response to a diagnosis of a disorder or its symptoms (e.g., a diagnosis or symptoms of an episode of depression, major depressive disorder, bipolar depression, anxiety, or postpartum depression). In some embodiments, major depressive disorder is moderate major depressive disorder. In some embodiments, major depressive disorder is severe major depressive disorder. In some embodiments, the compound is formulated as individual dosing units (each unit comprising the compound of formula (I) and one or more appropriate pharmaceutically acceptable excipients). In some embodiments, the duration of the episodic dosing regimen is several weeks (e.g., about eight weeks). In contrast to chronic dosing as defined herein, episodic dosing of the compound is performed over a limited period of time (e.g., about two weeks to about eight weeks) in response to a diagnosis of a disorder (e.g., depression or its symptoms). In some embodiments, onset medication is administered once daily over several weeks (e.g., approximately 2 to 6 weeks). In one embodiment, the onset medication period is 2 weeks. In some embodiments, one or more onset medication regimens (e.g., two or more onset regimens) are administered to the subject over the lifetime of the subject.

[0100] compound It should be recognized that the formulas described herein may refer to specific carbon atoms (C17, C3, C19, etc.). These references are based on the position of the carbon atom according to the steroid nomenclature known and used in the industry, as shown below: [ka] . For example, C17 refers to the carbon atom at position 17, and C3 refers to the carbon atom at position 3.

[0101] In some embodiments, formula (I): [ka] a compound or a pharmaceutically acceptable salt thereof, wherein in formula (I),

Chemical formula

[0102] In some embodiments, formula (IX): [ka] A compound of, [ka] When the bond valency is permissible, it represents a single or double bond; R 2a , R 2b , R 4a , R 4b , R6 , R 7 , R 11a , and R 11b each independently is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 where, in each case, R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when bonded to an oxygen atom, a nitrogen protecting group when bonded to a nitrogen atom, or two R D1 groups are bonded to form a substituted or unsubstituted heterocyclic ring; or R 2a and R 2b , R 4a and R 4b , R 7a and R 7b , R 11a and R 11b any one of which is bonded to form an oxo (=O) group; R 16 and R 17 each independently is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2, -N(R A1 ), -CN(R A1 )2, -C(O)R A1 , -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SRA1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 -SC(=O)SR A1 -SC(=O)N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2 R A2 -OS(=O)2OR A1 -SS(=O)2R A2 -SS(=O)2OR A1 -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 And here, R in each case A1 These are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group when bonded to an oxygen atom, sulfur protecting group when bonded to a sulfur atom, nitrogen protecting group when bonded to a nitrogen atom, -SO2R A2 , -C(O)R A2 is either or two R A1 They combine to form substituted or unsubstituted heterocyclic rings or heteroaryl rings; R A2 is 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; R 3 is hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; [ka] If both are single bonds, R 5 is hydrogen or methyl; [ka] If one of them is a double bond, R 5 It does not exist; R 19 is hydrogen or methyl; R X These are independently hydrogen, or substituted or unsubstituted alkyl groups. R Y Compounds or pharmaceutically acceptable salts thereof, wherein are independently substituted or unsubstituted heteroaryls, are provided herein.

[0103] In some embodiments, formula (I-1): [ka] A compound of, [ka] When the bond valency is permissible, it represents a single or double bond; R 2a , R 2b , R 4a , R 4b , R 6 , R 7 , R 11a , and R 11b Each of these independently consists of hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, -OR D1 -OC(=O)R D1 -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 And here, R in each case D1These are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, and substituted ku is an unsubstituted aryl, or a substituted or unsubstituted heteroaryl, an oxygen protecting group when bonded to an oxygen atom, a nitrogen protecting group when bonded to a nitrogen atom, or two R D1 The groups bond to form substituted or unsubstituted heterocyclic rings; or R 2a and R 2b , R 4a and R 4b , R 7a and R 7b , R 11a and R 11b One of these combines to form an oxo (=O) group; R 16 and R 17 Each of these is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2, -N(R A1 ), -CN(R A1 )2, -C(O)R A1 -OC(=O)R A1 , -OC(=O)OR A1 -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 -SC(=O)SR A1 -SC(=O)N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2R A2 -OS(=O)2ORA1 -SS(=O)2R A2 -SS(=O)2OR A1 -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 And here, R in each case A1 These are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group when bonded to an oxygen atom, sulfur protecting group when bonded to a sulfur atom, nitrogen protecting group when bonded to a nitrogen atom, -SO2R A2 , -C(O)R A2 is either or two R A1 They combine to form substituted or unsubstituted heterocyclic rings or heteroaryl rings; R A2 is 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; R 3 is hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; [ka] If both are single bonds, R 5 is hydrogen; [ka] If one of them is a double bond, R 5 It does not exist; R 19 is hydrogen or methyl; R XThese are independently hydrogen, or substituted or unsubstituted alkyl groups. R Y Compounds or pharmaceutically acceptable salts thereof, wherein are independently substituted or unsubstituted heteroaryls, are provided herein. R 2a and R 2b base

[0104] In some embodiments, R 2a and R 2b Each of these independently consists of hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 -OC(=O)R D1 -NH2, or -N(R D1 )2, where R in each case D1 These are independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0105] In some embodiments, R 2a and R 2b Each of these is independently hydrogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 haloalkyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C1-C6 alkoxyhalo group, or an -OH group.

[0106] In some embodiments, R 2a and R 2b These are, independently, hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0107] In some embodiments, R 2a and R 2b Each of them is independently hydrogen.

[0108] In some embodiments, R 2a and R 2b Both are hydrogen. R4a and R 4b base In some embodiments, R 4a and R 4b Each is independently of the others, each independently of the others, hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 -OC(=O)R D1 -NH2, or -N(R D1 )2, where R in each case D1 These are independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0109] In some embodiments, R 4a and R 4b These are independently hydrogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 haloalkyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C1-C6 alkoxyhalo group, or an -OH group.

[0110] In some embodiments, R 4a and R 4b These are independently hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0111] In some embodiments, R 4a and R 4b Each of them is independently hydrogen.

[0112] In some embodiments, R 4a and R 4b Both are hydrogen. R 11a and R 11b base

[0113] In some embodiments, R 11a and R 11bEach of these independently consists of hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and -OR D1 -OC(=O)R D1 -NH2, or -N(R D1 )2, where R in each case D1 These are independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0114] In some embodiments, R 11a and R 11b These are independently hydrogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 haloalkyl group, a substituted or unsubstituted C1-C6 alkoxy group, or a substituted or unsubstituted C1-C6 alkoxyhalo group.

[0115] In some embodiments, R 11a and R 11b These are independently hydrogen, -CH3, -CH2CH3, -OCH3, or -CH(CH3)2.

[0116] In some embodiments, R 11a and R 11b Each of them is independently hydrogen.

[0117] In some embodiments, R 11a and R 11b Both are hydrogen. R 7 base

[0118] In some embodiments, R 7 This includes hydrogen, halogens, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 -OC(=O)R D1 -NH2, or -N(R D1 )2, where R in each case D1These are independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0119] In some embodiments, R 7 These are independently hydrogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 haloalkyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C1-C6 alkoxyhalo group, or an -OH group.

[0120] In some embodiments, R 7 These are independently hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0121] In some embodiments, R 7 It is hydrogen. R 6 base

[0122] In some embodiments, R 6 These are independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 -OC(=O)R D1 -NH2, or -N(R D1 )2, where R in each case D1 These are independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0123] In some embodiments, R 6 These are independently hydrogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 haloalkyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C1-C6 alkoxyhalo group, or an -OH group.

[0124] In some embodiments, R 6These are independently hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0125] In some embodiments, R 6 It is hydrogen. R 16 base

[0126] In some embodiments, R 16 These are independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 -OC(=O)R D1 -NH2, or -N(R D1 )2, where R in each case D1 These are independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0127] In some embodiments, R 16 These are independently hydrogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 haloalkyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C1-C6 alkoxyhalo group, or an -OH group.

[0128] In some embodiments, R 16 These are independently hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0129] In some embodiments, R 16 It is hydrogen. R 17 base

[0130] In some embodiments, R 17 These are independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 -OC(=O)R D1 -NH2, or -N(RD1 )2, where R in each case D1 These are independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0131] In some embodiments, R 17 Each of these is independently hydrogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 haloalkyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C1-C6 alkoxyhalo group, or an -OH group.

[0132] In some embodiments, R 17 These are independently hydrogen, -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0133] In some embodiments, R 17 It is hydrogen. R 19 base

[0134] In some embodiments, R 19 These are independently hydrogen, or substituted or unsubstituted C1-C6 alkyl groups.

[0135] In some embodiments, R 19 These are independently hydrogen, or substituted or unsubstituted C1-C4 alkyl groups.

[0136] In some embodiments, R 19 These are independently hydrogen, -CH3, -CH2CH3, or -CH2OCH(CH3)2.

[0137] In some embodiments, R 19 It is hydrogen.

[0138] In some embodiments, R 19 It is -CH2OCH(CH3)2.

[0139] In some embodiments, R 19 It is -CH3.

[0140] In some embodiments, R 19 It is -CH2CH3. R 3 base

[0141] In some embodiments, R 3 These are substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted carbocyclyl groups, or substituted or unsubstituted heterocyclyl groups.

[0142] In some embodiments, R 3 These are substituted or unsubstituted alkyl groups.

[0143] In some embodiments, R 3 These are substituted or unsubstituted C1-C6 alkyl groups.

[0144] In some embodiments, R 3 These are -CH2CH3 or -CH3, -CH2OCH2CH3, and -CH2OCH3.

[0145] In some embodiments, the compound of formula (I) is formula (Ia): [ka] A compound of or a pharmaceutically acceptable salt thereof, Here, R 1 These are substituted or unsubstituted alkyl groups. R 1 base

[0146] In some embodiments, R 1 These are C1-C6 alkyl groups.

[0147] In some embodiments, R 1 It is either -CH2CH3 or -CH3.

[0148] In some embodiments, R 1 It is -CH2CH3.

[0149] In some embodiments, R 1 It is -CH3. R 5 base

[0150] In some embodiments, the compound of formula (I) is formula (I-b1) or formula (I-b2): [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0151] In some embodiments, the compound of formula (I) is formula (I-c1) or formula (I-c2): [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0152] In some embodiments, the compound of formula (I) is formula (I-d1) or formula (I-d2): [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0153] In some embodiments, the compound of formula (I) is formula (I-d1): [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0154] In some embodiments, the compound of formula (I) is formula (I-d2): [ka] It is a compound of or a pharmaceutically acceptable salt thereof. R X base

[0155] In some embodiments, R X These are independently hydrogen, or substituted or unsubstituted C 1~6 It is alkyl.

[0156] In some embodiments, R X These are independently hydrogen, or substituted or unsubstituted C1-4 alkyl groups.

[0157] In some embodiments, R X These are independently hydrogen, -CH3, or -CH2CH3.

[0158] In some embodiments, R X It is hydrogen. R Y base

[0159] In some embodiments, the compound of formula (I) is formula (Ie): [ka] A compound of or a pharmaceutically acceptable salt thereof, where R Y It is a heteroaryl, and R 1 It is either -CH2CH3 or -CH3.

[0160] In some embodiments, R Y teeth, [ka] Selected from, Here, R in each case D These are independently hydrogen, halogen, -NO2, -CN, -OR GA , -N(R GA )2, -C(=O)R GA , -C(=O)OR GA -C(=O)N(R GA )2, -OC(=O)R GA , -OC(=O)OR GA , -N(R GA )C(=O)R GA, -OC(=O)N(R GA )2, -N(R GA )C(=O)OR GA -S(=O)2R GA -S(=O)2OR GA -OS(=O)2R GA -S(=O)2N(R GA )2, or -N(R GA )S(=O)2R GA , substitution or non-substitution C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, substituted or unsubstituted C 3~4 Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, C 5~10 A substituted or unsubstituted aryl, a substituted or unsubstituted 5- to 10-membered heteroaryl, or two R as needed GA These atoms combine with intervening atoms to form substituted or unsubstituted 3-4 membered carbocyclic or heterocyclic rings; Here, R in each case GA These are independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted, or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkinyl, substituted or unsubstituted C 3~6 Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group when bonded to oxygen, nitrogen protecting group when bonded to nitrogen, or two R GA The group combines with an intervening atom to form a substituted or unsubstituted carbocyclic ring or a heterocyclic ring; Here, R in each case X1 is hydrogen, or a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted carbocyclyl. e is 0, 1, 2, 3, 4, or 5.

[0161] In some embodiments, R Y teeth, [ka] Selected from.

[0162] In some embodiments, R D These are independently hydrogen, halogen, substituted or unsubstituted C 1~6 Alkyl, -CN, substituted or unsubstituted 5- to 6-membered heteroaryl, substituted or unsubstituted 5-membered heterocyclyl,

[0163] e is 0, 1, 2, 3, or 4.

[0164] In some embodiments, R Y teeth, [ka] Selected from, where R is -CH3, -CH2CH3, -i-Pr, cyclopropyl, or -CN.

[0165] In some embodiments, R Y teeth, [ka] Selected from.

[0166] In some embodiments, R Y teeth, [ka] That is the case.

[0167] In some embodiments, R Y teeth, [ka] That is the case.

[0168] In some embodiments, the compound of formula (I) is formula (If): [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0169] In some embodiments, the compound of formula (I) is of formula (Ig) [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0170] In some embodiments, the compound of formula (I) is a compound of formula (Ia), formula (I-b1), formula (I-b2), formula (I-c1), formula (I-c2), formula (I-d1), formula (I-d2), formula (Ie), formula (If), or formula (Ig).

[0171] In some embodiments, the pharmaceutical composition comprises compounds described herein or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients.

[0172] In some embodiments, in subjects requiring treatment for a CNS-related disorder, a method for treating the CNS-related disorder comprises administering to the subject an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the CNS-related disorder is a sleep disorder, mood disorder, schizophrenia spectrum disorder, seizure disorder, memory and / or cognitive impairment, motor disorder, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disorder, substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus. In some embodiments, the CNS-related disorder is depression. In certain embodiments, the CNS-related disorder is postpartum depression. In certain embodiments, the CNS-related disorder is major depressive disorder. In some embodiments, the major depressive disorder is moderate major depressive disorder. In some embodiments, the major depressive disorder is severe major depressive disorder.

[0173] In some embodiments, the compound is selected from the group consisting of the compounds specified in Table 1 below: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14]

[0174] In one aspect, what is provided herein are pharmaceutically acceptable salts of the compounds described herein (e.g., compounds of formula (I)).

[0175] In one aspect, provided herein are pharmaceutical compositions comprising a compound described herein (e.g., a compound of formula (I)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the compound of the present invention is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the compound of the present invention is provided in a therapeutically effective amount.

[0176] The compounds of the present invention described herein act, in certain embodiments, as GABA modulators that act, for example, on GABAA receptors in a positive or negative manner. Such compounds are expected to have CNS activity as modulators of central nervous system (CNS) excitability, mediated by their ability to modulate GABAA receptors.

[0177] Therefore, in another aspect, the present invention provides a method for treating a CNS-related disorder in a subject requiring treatment for a CNS-related disorder, comprising the step of administering an effective amount of the compound of the present invention to the subject. In certain embodiments, the CNS-related disorder is a sleep disorder, mood disorder, schizophrenia spectrum disorder, seizure disorder, memory and / or cognitive impairment, motor disorder, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disorder, substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus. In certain embodiments, the CNS-related disorder is depression. In certain embodiments, the CNS-related disorder is postpartum depression. In certain embodiments, the CNS-related disorder is major depressive disorder. In certain embodiments, the major depressive disorder is moderate major depressive disorder. In certain embodiments, the major depressive disorder is severe major depressive disorder. In certain embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered orally. In certain embodiments, the compound is administered chronically. In certain embodiments, the compound is administered continuously, for example, by continuous intravenous infusion.

[0178] Exemplary compounds of the present invention can be synthesized from the following known starting materials using methods known to those skilled in the art or certain references. In one aspect, what is provided herein are pharmaceutically acceptable salts of the compounds described herein (e.g., compounds of formula (I)).

[0179] Alternative Embodiments In alternative embodiments, the compounds described herein may also include one or more isotopic substitutions. For example, hydrogen may be, for example, 2 H(D or Deuterium) )or 3 It could be H (T or tritium); carbon, for example, 13 C or 14 It could be C; oxygen, for example, 18 It could be O; nitrogen, for example, 15 It could be N, etc. In other embodiments, a specific isotope (for example, 3 H, 13 C, 14 C, 18 O or 15 N) may correspond to at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of the element occupying a particular site of the compound. Pharmaceutical composition

[0180] In one aspect, the Specified Pharmaceutical Composition is provided herein, comprising a compound described herein (e.g., a compound of formula (I)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the compound of the present invention is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the compound of the present invention is provided in a therapeutically effective amount.

[0181] In certain embodiments, the pharmaceutical composition contains an effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition contains a therapeutically effective amount of the active ingredient.

[0182] The pharmaceutical compositions provided herein may be administered by various routes, including, but not limited to, oral (enteral), parenteral (injection), rectal, transdermal, intradermal, intrathin, subcutaneous (SC), intravenous (IV), intramuscular (IM), and intranasal.

[0183] Generally, the compounds provided herein are administered in effective doses. The actual amount of compound administered is typically determined by a physician in light of the relevant circumstances, including the symptoms being treated, the chosen route of administration, the specific compound administered, the individual patient's age, weight and response, and the severity of the patient's symptoms.

[0184] When used to prevent the development of CNS disorders, the compounds provided herein may typically be administered to subjects at risk of developing the symptoms at the dosage levels described above, with the advice and supervision of a physician. Subjects at risk of developing specific symptoms generally include those with a family history of the symptoms or those identified by genetic testing or screening as particularly susceptible to developing the symptoms.

[0185] The pharmaceutical compositions provided herein are also intended for long-term administration ("long-term administration"). Long-term administration means the administration of a compound or its pharmaceutical composition over a long period of time, for example, three months, six months, one year, two years, three years, five years, or can be continued indefinitely, for example, over the remainder of the subject's life. In certain embodiments, long-term administration is intended to provide a certain level of the compound in the blood over a long period of time, for example, within the therapeutic window.

[0186] The pharmaceutical compositions of the present invention may be delivered using various methods of administration. For example, in certain embodiments, the pharmaceutical composition may be given as a bolus, for example, for the purpose of increasing the concentration of the compound in the blood to an effective level. The placement of the bolus dose depends on the systemic level of the desired active ingredient throughout the body. For example, intramuscular or subcutaneous bolus doses allow for the slow release of the active ingredient, while boluses delivered directly to the veins (e.g., by IV drops) allow for faster delivery, which increases the concentration of the active ingredient in the blood. The concentration of the component is rapidly increased to an effective level. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, for example by IV drip, to provide maintenance of a steady-state concentration of the active ingredient in the subject's body. Furthermore, in yet another embodiment, the pharmaceutical composition may be administered first as a bolus dose, followed by continuous infusions.

[0187] Compositions for oral administration may take the form of a bulk liquid solution or suspension or a bulk powder. However, more generally, compositions are provided in unit dosage forms to facilitate precise administration. The term “unit dosage form” refers to a physically discontinuous unit suitable as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect together with suitable pharmaceutically acceptable excipients. Typical unit dosage forms include pre-measured and pre-filled ampoules or syringes for liquid compositions, or pills, tablets, capsules, etc., for solid compositions. In such compositions, the compound is usually present in small amounts (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various vehicles or excipients and processing aids that help form the desired dosage form.

[0188] For oral administration, a typical regimen involves 1 to 5 oral doses per day, particularly 2 to 4 doses, and usually 3 oral doses. When using these dosing patterns, each dose yields approximately 0.01 to approximately 20 mg / kg of the compound provided herein, with preferred doses yielding approximately 0.1 to approximately 10 mg / kg, particularly approximately 1 to approximately 5 mg / kg.

[0189] Transdermal doses are generally selected to provide blood levels similar to or lower than those achieved using injectable doses, and are generally in the range of about 0.01% to about 20% by weight, preferably about 0.1% to about 20% by weight, preferably about 0.1% to about 10% by weight, and more preferably about 0.5% to about 15% by weight.

[0190] The dose levels of the injectable agent range from approximately 0.1 mg / kg / hour to at least 20 mg / kg / hour, all over a period of approximately 1 to 120 hours, particularly 24 to 96 hours. Preloading bolus of approximately 0.1 mg / kg to 10 mg / kg or more may also be administered to achieve an appropriate steady-state level. The maximum total dose is not expected to exceed approximately 5 g / day for human patients weighing 40-80 kg.

[0191] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle containing buffers, suspending agents and dispensing agents, colorants, flavorings, etc. Solid forms may include, for example, any of the following components or compounds of similar properties: binders (e.g., microcrystalline cellulose, tragacanth gum or gelatin); excipients (e.g., starch or lactose); disintegrants (e.g., alginic acid, Primogel or corn starch); lubricants (e.g., magnesium stearate); lubricants (e.g., colloidal silicon dioxide); sweeteners (e.g., sucrose or saccharin); or flavorings (e.g., peppermint, methyl salicylate or orange flavor).

[0192] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline or other injectable excipients known in the art. As is conventional, the active compound in such compositions is typically a trace component, often about 0.05–10% by weight, with the remainder being injectable excipients, etc.

[0193] Transdermal compositions are typically formulated as topical ointments or creams containing one or more active ingredients. When formulated as an ointment, the active ingredients are typically... It is miscible with a lafin ointment base or a water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream, for example, containing an oil-in-water cream base. Such transdermal formulations are well known in the art and generally include further components that enhance the skin penetration or stability of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope provided herein.

[0194] The compounds provided herein may also be administered by transdermal devices. Therefore, transdermal administration can be achieved using reservoir-type, porous membrane-type, or solid matrix-type patches.

[0195] The components described above for orally, injectably, or topically administered compositions are merely representative. Other materials and processing methods are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania (as incorporated herein by reference).

[0196] The compounds of the present invention may also be administered in sustained-release form or via sustained-release drug delivery systems. A description of typical sustained-release materials can be found in Remington's Pharmaceutical Sciences.

[0197] The present invention also relates to pharmaceutically acceptable acid addition salts of the compounds of the present invention. Acids that can be used to prepare pharmaceutically acceptable salts are those that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions (e.g., hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, p-toluenesulfonate, etc.).

[0198] In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable excipient (for example, a composition suitable for injection, such as intravenous (IV) administration).

[0199] Pharmaceutically acceptable excipients include any diluent or other liquid vehicle suitable for injection, such as any desired specific dosage form, dispersing or suspending agent, surfactants, isotonic agents, preservatives, and lubricants. General considerations for the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington's Pharmaceutical Sciences, 16th edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980) and Remington: The Science and Practice of Pharmacy, 21st edition (Lippincott Williams & Wilkins, 2005).

[0200] For example, preparations for injection, such as sterile aqueous suspensions for injection, can be formulated by known techniques using appropriate dispersants or wetting and suspending agents. Exemplary excipients that may be used include, but are not limited to, water, sterile saline or phosphate-buffered saline, or Ringer's solution.

[0201] In certain embodiments, the pharmaceutical composition further comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, each consisting of 6, 7, and 8 α-1,4-linked glucose units, with optionally one or more substituents (including, but not limited to, substituted or unsubstituted methylation, hydroxyalkylation, acylation, and sulfoalkyl ether substitution) on the linked sugar moiety. In certain embodiments, cyclodextrin Thrin is a sulfoalkyl ether β-cyclodextrin, for example, a sulfobutyl ether β-cyclodextrin also known as CAPTISOL®. See, for example, U.S. Patent No. 5,376,645. In certain embodiments, the composition comprises hexapropyl-β-cyclodextrin. In more specific embodiments, the composition comprises hexapropyl-β-cyclodextrin (10-50% in water).

[0202] The injectable composition may be sterilized, for example, by filtration using a bacterial-retaining filter, or by incorporating a sterilizer in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0203] Generally, the compounds provided herein are administered in effective doses. The actual amount of compound administered is typically determined by a physician in light of the relevant circumstances, including the symptoms being treated, the chosen route of administration, the actual compound administered, the individual patient's age, weight, response, and the severity of the patient's symptoms.

[0204] The composition is provided in unit dosage forms to facilitate precise administration. The term “unit dosage form” refers to a physically discontinuous unit appropriate as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect, along with appropriate pharmaceutically acceptable excipients. Typical unit dosage forms include pre-measured and pre-filled ampoules or syringes of liquid compositions. In such compositions, the compound is usually present in small amounts (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various vehicles or carriers and processing aids that help form the desired dosage form.

[0205] The compounds provided herein may be administered as single activators or in combination with other activators. In one aspect, the present invention provides combinations of the compounds of the present invention with another pharmacologically active agent. Dosage in combination may be carried out by any technique apparent to those skilled in the art (e.g., separate administration, sequential administration, simultaneous administration, and alternating administration).

[0206] The descriptions of pharmaceutical compositions provided herein primarily concern those suitable for administration to humans; however, those skilled in the art will understand that such compositions are generally suitable for administration to all types of animals. Modifications of pharmaceutical compositions suitable for administration to humans to compositions suitable for administration to various animals are well understood, and a veterinary pharmacologist of ordinary knowledge can design and / or carry out such modifications in ordinary experiments. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy. It can be found in the 21st edition, Lippincott Williams & Wilkins, 2005.

[0207] In one aspect, a kit is provided that includes a composition (e.g., a solid composition) containing a compound of formula (I).

[0208] Instructions for use and handling In certain contexts, the compounds described herein (e.g., compounds of formula (I)) are useful as therapeutic agents for treating CNS-related disorders (e.g., sleep disorders, mood disorders (e.g., depression), schizophrenia spectrum disorder, seizure disorders, epilepsy, memory and / or cognitive impairments, motor disorders, personality disorders, autism spectrum disorder, pain, traumatic brain injury, vascular disorders, substance abuse disorders and / or withdrawal syndromes, or tinnitus) in subjects in need (e.g., subjects with Rett syndrome, fragile X syndrome, or Angelman syndrome). It is assumed that this is the case. Exemplary CNS conditions associated with GABA regulation include sleep disorders [e.g., insomnia], mood disorders [e.g., depression (e.g., major depressive disorder (MDD)), dysthymic disorder (e.g., mild depression), bipolar disorder (e.g., type I and / or type II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (e.g., obsessive-compulsive disorder (OCD))], schizophrenia spectrum disorders [e.g., schizophrenia, schizoaffective disorder], seizure disorders [e.g., epilepsy (e.g., status epilepticus (SE)), seizures], memory and / or cognitive impairments [e.g., attention deficit (e.g., attention deficit hyperactivity disorder (ADHD)), dementia (e.g., Alzheimer's disease, Lewis body type dementia)]. This includes, but is not limited to, dementia, vascular dementia, motor disorders (e.g., Huntington's disease, Parkinson's disease), personality disorders (e.g., antisocial personality disorder, obsessive-compulsive personality disorder), autism spectrum disorder (ASD) (e.g., autism, one-host causes of autism such as synaptic degeneration (e.g., Rett syndrome, fragile X syndrome, Angelman syndrome)), pain (e.g., neuropathic pain, injury-related pain syndrome, acute pain, chronic pain), traumatic brain injury (TBI), vascular disorders (e.g., stroke, ischemia, vascular malformations), substance abuse disorders and / or withdrawal syndromes (e.g., addiction to opioid preparations, cocaine, and / or alcohol)), and tinnitus.

[0209] In certain embodiments, CNS-related disorders are sleep disorders, mood disorders, schizophrenia spectrum disorders, seizure disorders, memory and / or cognitive impairments, motor disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular disorders, substance abuse disorders and / or withdrawal syndromes, tinnitus, or status epilepticus. In certain embodiments, CNS-related disorders are depression. In certain embodiments, CNS-related disorders are postpartum depression. In certain embodiments, CNS-related disorders are major depressive disorders. In certain embodiments, major depressive disorders are moderate major depressive disorders. In certain embodiments, major depressive disorders are severe major depressive disorders.

[0210] In one aspect, a method is provided for reducing or preventing seizure activity in a subject, the method comprising the step of administering an effective amount of the compound of the present invention to a subject requiring such treatment. In some embodiments, the method reduces or prevents the occurrence of epilepsy.

[0211] In another context, combinations of the compounds of the present invention with other pharmacologically active agents are provided. The compounds provided herein may be administered as single activators or in combination with other agents. Combination administration may be carried out by any technique apparent to those skilled in the art (e.g., separate administration, sequential administration, simultaneous administration, and alternating administration).

[0212] In another context, a method is provided for treating or preventing brain excitation in a subject who is susceptible to or suffering from a condition related to brain excitation, the method comprising the step of administering to the subject an effective amount of the compound of the present invention.

[0213] In another context, a method is provided for treating or preventing stress or anxiety in a subject, the method comprising administering an effective amount of the compound or composition of the present invention to a subject in need of such treatment.

[0214] In another context, a method is provided for reducing or preventing insomnia in a subject, the method comprising administering an effective amount of the compound or composition of the present invention to a subject in need of such treatment.

[0215] In another context, a method is provided for inducing sleep and substantially maintaining the level of REM sleep observed in normal sleep, without inducing substantial rebound insomnia, the method comprising the step of administering an effective amount of the compound of the present invention.

[0216] In another context, a method is provided for reducing or preventing premenstrual syndrome (PMS) or postpartum depression (PND) in subjects, the method comprising the step of administering an effective amount of the compound of the present invention to a subject in need of such treatment.

[0217] In another context, a method is provided for treating or preventing a mood disorder in a subject, comprising the step of administering an effective amount of the compound of the present invention to a subject in need of such treatment. In a particular embodiment, the mood disorder is depression.

[0218] In another context, a method is provided for treating cognitive enhancement or memory impairment by administering a therapeutically effective amount of the compound of the present invention to a subject. In certain embodiments, the disorder is Alzheimer's disease. In certain embodiments, the disorder is Rett syndrome.

[0219] In another context, a method is provided for treating attention disorders by administering a therapeutically effective amount of the compound of the present invention to a subject. In a particular embodiment, this attention disorder is ADHD.

[0220] In certain embodiments, the compound is administered to the subject over a long period of time. In certain embodiments, the compound is administered to the subject orally, subcutaneously, intramuscularly, or intravenously.

[0221] Neuroendocrine disorders and dysfunctions Methods that may be used to treat neuroendocrine disorders and dysfunctions are provided herein. As used herein, “neuroendocrine disorder” or “neuroendocrine dysfunction” refers to a range of conditions caused by imbalances in the production of hormones in the body that are directly related to the brain. Neuroendocrine disorders involve interactions between the nervous and endocrine systems. Since the hypothalamus and pituitary gland are two regions of the brain that control hormone production, damage to the hypothalamus or pituitary gland, for example, due to traumatic brain injury, can affect hormone production and other neuroendocrine functions of the brain. In some embodiments, the neuroendocrine disorder or dysfunction is associated with a women’s health disorder or condition (e.g., the women’s health disorders or conditions described herein). In some embodiments, the neuroendocrine disorder or dysfunction associated with a women’s health disorder or condition is polycystic ovary syndrome.

[0222] Symptoms of neuroendocrine disorders include, but are not limited to, behavioral, emotional, and sleep-related symptoms, reproductive function-related symptoms, and physical symptoms, including, but are not limited to, fatigue, memory impairment, anxiety, depression, weight gain or loss, emotional instability, lack of concentration, difficulty concentrating, loss of lipids, infertility, amenorrhea, decreased muscle mass, increased abdominal fat, hypotension, low heart rate, hair loss, anemia, constipation, cold intolerance, and dry skin.

[0223] Neurodegenerative diseases and disorders Methods that may be used to treat neurodegenerative diseases and disorders are provided herein. The term “neurodegenerative disease” encompasses diseases and disorders associated with the progressive loss of structure or function of neurons, or the death of neurons. Neurodegenerative diseases and disorders include Alzheimer’s disease (including symptoms associated with mild, moderate, or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic injuries; ataxia and convulsions. (including for treatment and prevention, and for the prevention of seizures caused by schizoaffective disorder or by drugs used to treat schizophrenia); benign amnesia; hydrocephalus; cerebellar ataxia (including McLeod neuroacanthocytosis syndrome (MLS)); closed head trauma; coma; contusion injuries (e.g., spinal cord injury and head injury); dementia (including multiple stroke dementia and senile dementia); impaired consciousness; Down syndrome; drug-induced or medication-induced tremor paralysis (e.g., acute sitting unsteadiness, acute ataxia, tremor paralysis or tardive dyskinesia induced by psychotropic agents, neuroleptic malignant syndrome, or drug-induced postural tremor); epilepsy; fragile X syndrome; Gilles de la Tourette syndrome; Head trauma; hearing impairment and hearing loss; Huntington's disease; Lennox syndrome; levodopa-induced dyskinesia; intellectual disability; motor disorders including immobility and akinesia (rigidity) syndrome (including brainstem nerve calcification, corticobasal degeneration, multiple system atrophy, tremor palsy-ALS dementia complex, Parkinson's disease, post-encephalitis tremor palsy and progressive supranuclear palsy); disorders related to muscle spasticity and muscle spasticity or weakness (chorea (e.g., benign hereditary chorea, drug-induced chorea, hemiplegia, Huntington's disease, neuroacanthocytosis, Sydenham's chorea and symptomatic chorea), dyskinesia (including tics such as complex tics, simple tics and symptomatic tics), myoclonus (generalized myoclonus and focal syloclonus (focal) Neuronal injuries (including cyloclonus), tremors (e.g., resting tremor, postural tremor, and intention tremor), and ataxia (including axial ataxia, dystonic writer's cramp, hemiplegic ataxia, paroxysmal ataxia, and focal ataxia (e.g., blepharospasm, oromandibular dystonia, as well as spasmodic dysphonia and torticollis)); neuronal injuries (including eye injuries, retinopathy of the eye, or macular degeneration); stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia, and neurotoxic disorders after cardiac arrest; Parkinson's disease; seizures; status epilepticus; stroke; tinnitus;Neurodegenerative diseases include, but are not limited to, tubular sclerosis and neurodegeneration induced by viral infections (e.g., those caused by acquired immunodeficiency syndrome (AIDS) and brain damage). Other neurodegenerative diseases include, but are not limited to, stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia, and neurotoxic disorders following cardiac arrest. Methods for treating or preventing neurodegenerative diseases also include treating or preventing the loss of neuronal function characteristic of neurodegenerative disorders.

[0224] Mood disorder Methods for treating mood disorders, such as clinical depression, postpartum depression or postnatal depression, perinatal depression, atypical depression, melancholic depression, psychogenic major depression, catatonic depression, seasonal affective disorder, mood swings, double depression, depressive personality disorder, relapsing brief depression, minor depressive disorder, bipolar disorder or manic-depressive disorder, depression caused by chronic conditions, treatment-resistant depression, treatment-resistant depression, suicide, suicidal ideation or suicidal behavior are also provided herein. In some embodiments, the methods described herein provide a therapeutic effect on subjects suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is related to the diseases or disorders described herein (e.g., neuroendocrine diseases and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), motor disorders, tremors (e.g., Parkinson's disease), women's health disorders or health conditions).

[0225] Clinical depression, also known as major depressive disorder (MDD), unipolar depression, unipolar disorder, and recurrent depression, is a mental disorder characterized by pervasive and persistent depressed mood accompanied by low self-esteem and loss of interest or pleasure in activities that are normally enjoyable. Some people with clinical depression have difficulty sleeping, become thin, generally feel agitated, and become irritable. Clinical depression affects how an individual feels, thinks, and behaves and can lead to a range of emotional and physical problems. The body sometimes struggles to perform daily activities, and it can feel as if life is not worth living.

[0226] Perinatal depression refers to depression during pregnancy. Symptoms include irritability, crying, restlessness, difficulty sleeping, extreme fatigue (emotional and / or physical), changes in appetite, difficulty concentrating, increased anxiety and / or worry, feelings of wanting to be away from the infant and / or fetus, and loss of interest in previously enjoyable activities.

[0227] Postpartum depression (PND), also known as postpartum depression (PPD), is a type of clinical depression that affects women after childbirth. Symptoms may include grief, fatigue, changes in sleep and eating habits, decreased sexual desire, crying episodes, anxiety, and irritability. In some embodiments, PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein). In some embodiments, PND is treatment-refractory depression (e.g., treatment-refractory depression as described herein).

[0228] In some embodiments, subjects with PND also experience depression or symptoms of depression during pregnancy. This depression is referred to herein as perinatal depression. In some embodiments, subjects who experience perinatal depression are at higher risk of experiencing PND.

[0229] Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anhedonia) and positivity, marked weight gain or increased appetite. Patients with AD may also have significant social impairment as a result of excessive sleepiness or somnolence (hypersomnia), heaviness in the limbs, and hypersensitivity to perceived social rejection.

[0230] Melancholic depression is characterized by a loss of pleasure from almost or all activities (anhedonic syndrome), unresponsiveness to pleasant stimuli, depressed mood that is more pronounced than feelings of grief or loss, excessive weight loss, or excessive guilt.

[0231] Psychotic major depressive disorder (PMD), or psychotic depression, refers to a major depressive episode, particularly a melancholic major depressive episode, in which an individual experiences psychotic symptoms such as delusions and hallucinations.

[0232] Catastrophic depression refers to major depressive disorder accompanied by motor and behavioral impairments and other symptoms. Individuals may become mute, enter a stupor state, become immobile, or exhibit aimless or paranoid movements.

[0233] Seasonal affective disorder (SAD) is a type of seasonal depression in which individuals experience depressive episodes that follow a seasonal pattern, typically occurring in the fall or winter.

[0234] Mood disorders refer to conditions associated with unipolar depression, where the same physical and cognitive problems are evident. They tend to be less severe and last longer (e.g., at least two years).

[0235] Bipolar disorder refers to a period of severe depression (mood disorder) that lasts for at least two years, interspersed with periods of major depression.

[0236] Depressive personality disorder (DPD) refers to a personality disorder characterized by depressive traits.

[0237] Recurrent Brief Depression (RB) D) refers to a condition in which an individual experiences a depressive episode approximately once a month, with each episode lasting for two weeks or less, typically less than two to three days.

[0238] Minor depressive disorder, or minor depression, refers to a type of depression in which at least two symptoms are present for two weeks.

[0239] Bipolar disorder, or manic-depressive disorder, is characterized by extreme mood swings, including high (manic or hypomanic) and low (depressive) periods. During manic episodes, individuals may feel or act unusually happy, energetic, or irritable. They often make impulsive decisions with little regard for consequences. Sleep needs are typically reduced. During depressive episodes, individuals may cry uncontrollably, avoid eye contact with others, and have a pessimistic outlook on life. The suicide risk for individuals with this disorder is high, over 6% over a 20-year period, and 30-40% engage in self-harm. Other mental health problems, such as anxiety disorders and substance use disorders, commonly comorbid bipolar disorder.

[0240] Depression caused by a chronic medical condition refers to depression that is triggered by a chronic medical condition such as cancer, chronic pain, chemotherapy, or chronic stress.

[0241] Treatment-resistant depression refers to a condition in which an individual receives treatment for depression but their symptoms do not improve. For example, antidepressants or psychological counseling (psychotherapy) do not alleviate the depressive symptoms of individuals with treatment-resistant depression. In some cases, individuals with treatment-resistant depression improve their symptoms but then relapse. Treatment-resistant depression occurs in patients with depression that is resistant to standard pharmacological treatments, including tricyclic antidepressants, MAOIs, SSRIs, and double and triple reuptake inhibitors, as well as anxiolytics, and non-pharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagal stimulation, and / or transcranial magnetic stimulation).

[0242] Postoperative depression refers to a depressive state following a surgical procedure (for example, as a result of facing death). For example, an individual may experience persistent sadness or emptiness, loss of pleasure or interest in hobbies and activities they normally enjoyed, or persistent feelings of worthlessness or despair.

[0243] Mood disorders associated with women's health conditions or health problems refer to mood disorders (e.g., depression) associated with (e.g., caused by) women's health conditions or health problems (e.g., those described herein).

[0244] Suicidal tendencies, suicidal ideation, and suicidal behavior refer to an individual's tendency to commit suicide. Suicidal ideation relates to thoughts about suicide or an abnormal preoccupation with suicide. The range of suicidal ideation varies greatly, for example, from momentary thoughts to broader thoughts, detailed plans, role-playing, and unsuccessful attempts. Symptoms include talking about suicide, obtaining means to commit suicide, withdrawing from social contact, constantly thinking about death, feeling trapped or hopeless about a situation, increased alcohol or drug use, engaging in dangerous or self-destructive behavior, and saying goodbye to people as if never to see them again.

[0245] Symptoms of depression include persistent feelings of anxiety or sadness, helplessness, hopelessness, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, motor challenges, loss of interest in enjoyable activities or hobbies, difficulty concentrating, low energy, low self-esteem, lack of positive thoughts or plans, excessive sleep, overeating, loss of appetite, insomnia, self-harm, suicidal thoughts, and suicide attempts. The presence, severity, frequency, and duration of symptoms can vary from case to case. The symptoms of depression and their alleviation can be confirmed by a physician or psychologist (e.g., through mental health assessment).

[0246] In some embodiments, the method includes monitoring subjects using known depression scales, such as the Hamilton Depression-D scale, the Clinical Global Impression Improvement Scale (CGI), and the Montgomery-Asberg Depression Rating Scale (MADRS). In some embodiments, the therapeutic effect may be measured by a decrease in the subject's Hamilton Depression-D total score. This decrease in the HAM-D total score may occur within 4, 3, 2, or 1 day; or within 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, or 8 hours or less. The therapeutic effect may be evaluated over a specific treatment period. For example, therapeutic effect may be measured by a decrease in the HAM-D total score from baseline after administration of a compound described herein (e.g., a compound of formula (I)) (e.g., 12, 24, or 48 hours after administration; or 24, 48, 72, or 96 hours after administration or beyond; or 1, 2, 14, 21, or 28 days after administration; or 1, 2, 3, or 4 weeks after administration; or 1, 2, 6, or 10 months after administration; or 1, 2, or 1 year, or 2 years or over a lifetime).

[0247] In some embodiments, the subject has a mild depressive disorder, e.g., mild major depressive disorder. In some embodiments, the subject has a moderate depressive disorder, e.g., moderate major depressive disorder. In some embodiments, the subject has a severe depressive disorder, e.g., severe major depressive disorder. In some embodiments, the subject has a very severe depressive disorder, e.g., very severe major depressive disorder. In some embodiments, the subject's baseline HAM-D total score (i.e., before treatment with the compounds described herein (e.g., the compound of formula (I))) is at least 24. In some embodiments, the subject's baseline HAM-D total score is at least 18. In some embodiments, the subject's baseline HAM-D total score is between 14 and 18, including 14 and 18. In some embodiments, the subject's baseline HAM-D total score is between 19 and 22, including 19 and 22. In some embodiments, the total HAM-D score of a subject before treatment with a compound described herein (e.g., a compound of formula (I)) is greater than or equal to 23. In some embodiments, the baseline score is at least 10, 15, or 20. In some embodiments, the total HAM-D score of a subject after treatment with a compound described herein (e.g., a compound of formula (I)) is about 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8). In some embodiments, the total HAM-D score after treatment with a compound described herein (e.g., a compound of formula (I)) is 10, 7, 5, or less than 3. In some embodiments, the reduction in the HAM-D total score is a decrease from a baseline score of about 20–30 (e.g., 22–28, 23–27, 24–27, 25–27, 26–27) to a HAM-D total score of about 0–10 (e.g., less than 10; 0–10, 0–6, 0–4, 0–3, 0–2, or 1.8) after treatment with a compound described herein (e.g., a compound of formula (I)).In some embodiments, the reduction from the baseline HAM-D total score to the HAM-D total score after treatment with a compound described herein (e.g., a compound of formula (I)) is at least 1, 2, 3, 4, 5, 7, 10, 25, 40, 50, or 100 times. In some embodiments, the percentage reduction from the baseline HAM-D total score to the HAM-D total score after treatment with a compound described herein (e.g., a compound of formula (I)) is at least 50% (e.g., 60%, 70%, 80%, or 90%). In some embodiments, the therapeutic effect is measured as a reduction in the HAM-D total score after treatment with a compound described herein (e.g., a compound of formula (I)) compared to the baseline HAM-D total score (e.g., 12, 24, 48 hours after administration; or 24, 48, 72, 96 hours or more after administration; or 1, 2, 14 days or more after administration), and is at least 10, 15, or 20 points.

[0248] In some embodiments, a method for treating a depressive disorder, such as major depressive disorder, provides a therapeutic effect (e.g., as measured by a decrease in the Hamilton Depression Rating Scale (HAM-D)) within 14, 10, 4, 3, 2, or 1 day or within 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, a method for treating a depressive disorder, such as major depressive disorder, provides a therapeutic effect (e.g., as determined by a statistically significant decrease in the HAM-D total score) within 1 or 2 days of treatment with a compound described herein (e.g., a compound of formula (I)). In some embodiments, a method for treating a depressive disorder, such as major depressive disorder, provides a therapeutic effect (e.g., as determined by a statistically significant decrease in the HAM-D total score) within 14 days or equal to 14 days from the start of treatment with a compound described herein (e.g., a compound of formula (I)). In some embodiments, a method for treating a depressive disorder, such as major depressive disorder, provides a therapeutic effect (e.g., as determined by a statistically significant decrease in the HAM-D total score) within a period of less than 21 days or equal to 21 days from the start of treatment with a compound described herein (e.g., a compound of formula (I)). In some embodiments, a method for treating a depressive disorder, such as major depressive disorder, provides a therapeutic effect (e.g., as determined by a statistically significant decrease in the HAM-D total score) within a period of less than 28 days or equal to 28 days from the start of treatment with a compound described herein (e.g., a compound of formula (I)). In some embodiments, the therapeutic effect is a decrease from baseline in the HAM-D total score after treatment with a compound described herein (e.g., a compound of formula (I)) (e.g., treatment with compound 1 once daily for 14 days). In some embodiments, the subject's HAM-D total score before treatment with a compound described herein (e.g., a compound of formula (I)) is at least 24. In some embodiments, the total HAM-D score of the subject before treatment with the compounds described herein (e.g., the compound of formula (I)) is at least 18.In some embodiments, the HAM-D total score of a subject before treatment with a compound described herein (e.g., a compound of formula (I)) is between 14 and 18, including 14 and 18. In some embodiments, the decrease in the HAM-D total score after treatment of the subject with a compound described herein (e.g., a compound of formula (I)) compared to the baseline HAM-D total score is at least 10. In some embodiments, the decrease in the HAM-D total score after treatment of the subject with a compound described herein (e.g., a compound of formula (I)) compared to the baseline HAM-D total score is at least 15 (e.g., at least 17). In some embodiments, the HAM-D total score associated with treatment of a subject with a compound described herein (e.g., a compound of formula (I)) is a number in the range of 6 to 8 or less. In some embodiments, the HAM-D total score associated with treatment of a subject with a compound described herein (e.g., a compound of formula (I)) is 7 or less.

[0249] In some embodiments, the method provides a therapeutic effect (e.g., measured by a decrease in the Clinical Global Impression Improvement Scale (CGI)) within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours, or less. In some embodiments, the CNS disorder is a depressive disorder, e.g., major depressive disorder. In some embodiments, the method for treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic effect within 2 days of the treatment period. In some embodiments, the therapeutic effect is a decrease in the CGI score from baseline at the end of the treatment period (e.g., 14 days after administration).

[0250] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a decline in the Montgomery-Asberg Depression Rating Scale (MADRS)) within 14, 10, 4, 3, 2, or 1 day or within 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, the CNS disorder is a depressive disorder, such as major depressive disorder. The treatment method provides a therapeutic effect within two days of the treatment period. In some embodiments, the therapeutic effect is a reduction in the MADRS score from baseline at the end of the treatment period (e.g., 14 days after administration).

[0251] The effectiveness of treatment for major depressive disorder can be determined by a decrease in the subject's Montgomery-Asberg Depression Rating Scale (MADRS) score. For example, the MADRS score may decrease within 4, 3, 2, or 1 day; or within 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, or 8 hours or less. The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item diagnostic questionnaire used by psychiatrists to measure the severity of depressive episodes in patients with mood disorders, relating to outwardly expressed sadness, verbal sadness, internal tension, decreased sleep, decreased appetite, difficulty concentrating, fatigue, inability to feel, pessimistic thinking, and suicidal thoughts.

[0252] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a decline in the Edinburgh Postnatal Depression Scale (EPDS)) within 4 days, 3 days, 2 days, 1 day; 24 hours, 20 hours, 16 hours, 12 hours, 10 hours, 8 hours, or less. In some embodiments, the therapeutic effect is an improvement as measured by the EPDS.

[0253] In some embodiments, the method provides therapeutic effects (e.g., as measured by a decrease in the Generalized Anxiety Disorder 7-Item Scale (GAD-7)) within 4 days, 3 days, 2 days, 1 day; 24 hours, 20 hours, 16 hours, 12 hours, 10 hours, 8 hours, or less.

[0254] Anxiety disorder Methods for treating anxiety disorders (e.g., generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, phobias, post-traumatic stress disorder) are provided herein. Anxiety disorder is a broad term encompassing several different forms of abnormal and pathological fears and anxieties. Current psychiatric diagnostic criteria recognize a wide range of anxiety disorders.

[0255] Generalized anxiety disorder (GPD) is a generalized chronic disorder characterized by persistent anxiety that cannot be focused on any single object or situation. People suffering from GPD experience nonspecific, persistent fears and worries, and tend to worry excessively about ordinary things. GPD is the most common anxiety disorder affecting older adults.

[0256] In panic disorder, individuals suffer from short bursts of intense fear and anxiety, often characterized by tremors, shaking, confusion, dizziness, nausea, and shortness of breath. These panic attacks (defined by APA as sudden fear or discomfort that peaks in less than 10 minutes) can last for several hours and can be triggered by stress, fear, or even exercise, although a specific cause is not always apparent. In addition to recurrent, unpredictable panic attacks, a diagnosis of phobic disorder also requires that the attacks have chronic consequences (either worry about the potential implications of the attack, persistent fear of future attacks, or significant behavioral changes related to the attack). Thus, individuals with phobic disorder experience symptoms even outside the scope of a particular panic episode. Often, unusual changes in heart rate are noticed by those suffering from panic, leading them to believe that their heart is malfunctioning or that they are about to experience another panic attack. In some cases, heightened perception of bodily functions (hypervigilance) occurs during panic attacks, in which case any perceived physiological changes are interpreted as a potentially life-threatening illness (i.e., excessive hypochondria).

[0257] Obsessive-compulsive disorder (OCD) is a type of anxiety disorder primarily characterized by recurrent obsessions (urgent, persistent, and disturbing thoughts or images) and compulsive behaviors (the urge to perform specific actions or rituals). OCD thought patterns can be linked to superstition insofar as they involve the person believing in causal relationships that do not actually exist. Often, the process is entirely illogical. For example, the compulsion to walk in a specific pattern may be used to alleviate an obsession with imminent danger. And in many cases, this compulsion is not entirely inexplicable, but simply an urge to complete a neurotic-induced ritual. In a small number of cases, individuals with OCD may experience only obsessions without overt compulsions, and in even fewer, only compulsions.

[0258] One of the largest categories of anxiety disorders is phobias, which encompass all cases in which fear and anxiety are triggered by a specific stimulus or situation. Patients typically anticipate terrifying consequences from encountering their object of fear (which can range from animals, places, to bodily fluids).

[0259] Post-traumatic stress disorder, or PTSD, is an anxiety disorder resulting from a traumatic experience. Post-traumatic stress can arise from extreme situations (e.g., war, rape, hostage situations, or even major disasters). It can also result from prolonged (chronic) exposure to severe stressors (e.g., soldiers who can tolerate individual battles but cannot cope with continuous warfare). Common symptoms include flashbacks, avoidance behaviors, and depression.

[0260] Women's health problems Methods for treating conditions or disorders related to women's health are provided herein. Conditions or disorders related to women's health include, but are not limited to, gynecological health and disorders (e.g., premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD)), pregnancy-related problems (e.g., miscarriage, abortion), infertility and related disorders (e.g., polycystic ovary syndrome (PCOS)), other disorders and conditions, and problems related to women's overall health and well-being (e.g., menopause).

[0261] Gynecological health issues affecting women include menstruation and menstrual irregularities; urinary tract health (including urinary incontinence and pelvic floor disorders); and conditions such as bacterial vaginosis, vaginitis, uterine fibrosis, and vulvodysia.

[0262] Premenstrual syndrome (PMS) refers to physical and emotional symptoms that occur one to two weeks before menstruation. Symptoms vary but may include bleeding, mood swings, breast tenderness, bulimia, fatigue, irritability, acne, and depression.

[0263] Premenstrual dysphoric disorder (PMDD) is a severe form of PMS. The symptoms of PMDD are similar to those of PMS but are more severe and can interfere with work, social activities, and relationships. Symptoms of PMDD include mood swings, depressed mood or feelings of hopelessness, marked anger, increased interpersonal conflict, tension and anxiety, irritability, decreased interest in usual activities, difficulty concentrating, fatigue, changes in appetite, feelings of uncontrollability or confusion, sleep problems, and physical problems (e.g., bloating, breast tenderness or swelling, headache, joint pain or muscle pain).

[0264] Pregnancy-related issues include prenatal and prenatal care, pregnancy loss (miscarriage and stillbirth), premature birth and early delivery, sudden infant death syndrome (SIDS), breastfeeding, and birth defects.

[0265] A miscarriage refers to the spontaneous termination of a pregnancy within 20 weeks of gestation.

[0266] Abortion refers to the intentional termination of a pregnancy, which can be performed up to 28 weeks of gestation.

[0267] Infertility and related disorders include uterine fibrosis, polycystic ovary syndrome, endometriosis, and primary ovarian dysfunction.

[0268] Polycystic ovary syndrome (PCOS) refers to an endocrine disorder in women of reproductive age. PCOS is a set of symptoms resulting from elevated levels of male hormones in women. Many women with PCOS develop numerous small cysts on their ovaries. Symptoms of PCOS include irregular or absent menstruation, heavy periods, excessive body and facial hair, acne, pelvic pain, difficulty conceiving, and thickened, dark, smooth skin patches. PCOS may be associated with conditions such as type 2 diabetes, obesity, obstructive sleep apnea, heart disease, mood disorders, and endometrial cancer.

[0269] Other disorders and conditions that affect only women include Turner syndrome, Rett syndrome, and ovarian and cervical cancer.

[0270] Issues related to women's overall health and well-being include violence against women, women with physical disabilities and unique challenges, osteoporosis and bone health, and menopause.

[0271] Menopause refers to the 12-month period following a woman's last menstrual period, marking the end of the menstrual cycle. Menopause typically occurs in women in their 40s or 50s. Menopausal symptoms, such as hot flashes and emotional disturbances, can disrupt sleep, reduce energy levels, or cause anxiety, sadness, or feelings of loss. Menopause can be spontaneous or surgical (induced by events such as surgery, e.g., hysterectomy, oophorectomy; cancer). Menopause can be induced, for example, when the ovaries are severely damaged by radiation, chemotherapy, or other drug therapies.

[0272] epilepsy Compounds of formula (I) or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable compositions thereof, may be used in the methods described herein, for example, in the treatment of disorders described herein, such as epilepsy, status epilepticus, or seizures.

[0273] Epilepsy is a brain disorder characterized by recurrent seizures over a long period of time. Types of epilepsy include, but are not limited to, generalized epilepsy, such as childhood absence epilepsy, juvenile myoclonus (nyoclonic) epilepsy, epilepsy with grand mal seizures while awake, West syndrome, Lennox-Gastaut syndrome, and partial epilepsy, such as temporal lobe epilepsy, frontal lobe epilepsy, and benign focal epilepsy in childhood.

[0274] Epilepsy occurs The compounds and methods described herein can be used to treat or prevent epilepsy development. Epilepsy development is a stepwise process in which a normal brain develops epilepsy (a chronic condition characterized by seizures). Epilepsy development arises from nerve damage caused by an initial injury (e.g., persistent status epilepticus).

[0275] Status epilepticus (SE) Status epilepticus (SE) includes, for example, convulsive status epilepticus, such as early status epilepticus, established status epilepticus, refractory status epilepticus, and extremely refractory status epilepticus; and non-convulsive status epilepticus, such as generalized status epilepticus. This can include status epilepticus, complex partial status epilepticus; generalized periodic epileptic discharges; and periodic unilateral epileptic discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epilepticus seizures and can include early status epilepticus, established status epilepticus, refractory status epilepticus, and extremely refractory status epilepticus. Early status epilepticus is treated with first-line therapy. Established status epilepticus is characterized by persistent status epilepticus seizures despite treatment with first-line therapy, and is treated with second-line therapy. Refractory status epilepticus is characterized by persistent status epilepticus seizures despite treatment with first-line and second-line therapy, and is generally treated with general anesthetics. Extremely refractory status epilepticus is characterized by seizures that persist despite first-line treatment, second-line treatment, and treatment with general anesthesia for 24 hours or more.

[0276] Nonconvulsive status epilepticus (NSE) can include, for example, focal NES, such as complex partial NES, simple partial NES, or micro NES; and generalized NES, such as late-onset absence NES, atypical absence NES, or typical absence NES.

[0277] The compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof may also be administered prophylactically to subjects having CNS disorders, e.g., traumatic brain injury, status epilepticus, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, extremely refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptic discharge; and periodic unilateral epileptic discharge, prior to the onset of a seizure.

[0278] seizure A seizure is a physical manifestation or change in behavior that follows an episode of abnormal electrical activity in the brain. The term “seizure” is often used interchangeably with “convulsion.” A convulsion is when a person’s body shakes rapidly and uncontrollably. During a convulsion, the person’s muscles repeatedly contract and relax.

[0279] Based on the type of behavior and brain activity, seizures are divided into two broad categories: generalized and partial (also called focal or localized). Classifying seizure types helps physicians diagnose whether or not a patient has epilepsy.

[0280] Generalized seizures are caused by electrical impulses from the entire brain, while partial seizures are caused (at least initially) by electrical impulses from a relatively small area of ​​the brain. The part of the brain that causes a seizure is sometimes called a lesion.

[0281] There are six types of generalized seizures. The most common, dramatic, and therefore most well-known is the generalized convulsion (also called a grand mal seizure). In this type of seizure, the patient loses consciousness and usually collapses. Following this loss of consciousness, there is a period of generalized rigidity (called the "tonic" phase of the seizure) for 30–60 seconds, followed by a period of intense spasms ("clonic" phase) for 30–60 seconds, after which the patient falls into a deep sleep ("postictal" or after-seizure phase). During a grand mal seizure, injuries and accidents (e.g., biting the tongue and urinary incontinence) can occur.

[0282] Absence seizures cause a brief (only a few seconds) loss of consciousness with little or no symptoms. Patients (most frequently children) typically interrupt their activities and... They stare blankly. These seizures begin and end suddenly and can occur several times a day. Patients are usually unaware they are having seizures unless they notice "losing time."

[0283] Myoclonic seizures consist of sporadic spasms, usually on both sides of the body. Patients sometimes describe these spasms as short electric shocks. In severe cases, these seizures can result in dropping or involuntarily throwing objects.

[0284] Clonic seizures are recurrent, rhythmic spasms that involve both sides of the body simultaneously.

[0285] Tonic seizures are characterized by muscle rigidity.

[0286] A toneacic attack consists of a sudden decrease in muscle tone throughout the body (especially in the arms and legs) and often leads to falls.

[0287] The seizures described herein may include epileptic seizures; acute recurrent seizures; cluster seizures; serial seizures; uninterrupted seizures; persistent seizures; recurrent seizures; status epilepticus, e.g., refractory convulsive status epilepticus, nonconvulsive status epilepticus; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondary generalized seizures; atypical absence seizures; absence seizures; astonic seizures; benign Rolandic seizures; febrile seizures; affective seizures; focal seizures; laughter seizures; generalized onset seizures; infantile spasms; Jackson's seizures; generalized bilateral myoclonic seizures; multifocal seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post-traumatic seizures; microseizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures. In some embodiments, the seizures are generalized seizures associated with Dravet syndrome, Lennox-Gastaut syndrome, compound tuberous sclerosis, Rett syndrome, or PCDH19 girl epilepsy.

[0288] Movement impairment Methods for treating motor disorders are also described herein. As used herein, “motor disorder” refers to a range of diseases and disorders associated with hyperkinetic disorders and abnormalities in the control of the muscles involved. Examples of motor disorders include, but are not limited to, Parkinson’s disease and tremor paralysis (defined especially by bradykinesia), dystonia, chorea and Huntington’s disease, ataxia, tremor (e.g., essential tremor), myoclonus and startle, tics and Tourette syndrome, restless legs syndrome, stiff person syndrome and gait disorders.

[0289] shaking The methods described herein may be used to treat tremors, for example, the compound of formula (I) may be used to treat, for example, cerebellar tremor or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, Parkinsonian tremor, physiological tremor, psychogenic tremor or rubral tremor. Tremors include hereditary, degenerative, and idiopathic disorders, such as Wilson's disease, Parkinson's disease, and essential tremor, respectively; metabolic disorders (e.g., thyroid-parathyroid disease, liver disease, and hypoglycemia); peripheral neuropathy (associated with Charcot-Marie-Tooth disease, Lucie-Lévy disease, diabetes mellitus, and complex focal pain syndrome); disorders induced by toxins (nicotine, mercury, lead, CO, manganese, arsenic, and toluene); disorders induced by drugs (hypnotics, tricyclic antidepressants, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, and vincristine); and psychogenic disorders. Clinical tremors include physiological tremors, fatigue-induced physiological tremors (enhanced physiologic tremor), and essential tremor. Tremors can be classified into tremor syndromes (including classical essential tremor, primary orthostatic tremor, and task-specific and postural tremor), dystonic tremor, Parkinsonian tremor, cerebellar tremor, Holmes tremor (i.e., red nucleus tremor), palatal tremor, neuropathic tremor, toxic or drug-induced tremor, and psychogenic tremor.

[0290] Tremors are involuntary, sometimes rhythmic, muscle contractions and relaxations that may involve vibration or spasms of one or more body parts (e.g., hands, arms, eyes, face, head, vocal cords, trunk, legs).

[0291] Cerebellar tremor, or intention tremor, is a slow, widespread tremor of the limbs that occurs after an intentional movement. Cerebellar tremors are caused by lesions or damage to the cerebellum, for example, resulting from tumors, strokes, or diseases (e.g., multiple sclerosis, hereditary degenerative disorders).

[0292] Dystonic tremors occur in individuals with dystonia, a movement disorder characterized by persistent, involuntary muscle contractions that cause twisting and repetitive movements and / or painful, abnormal postures or positions. Dystonic tremors can affect any muscle in the body. They occur irregularly and can often be relieved by complete rest.

[0293] Essential tremor, or benign essential tremor, is the most common type of tremor. Essential tremor can be mild and non-progressive in some cases, or it can be slowly progressive, starting on one side of the body but affecting both sides within three years. The hands are most frequently affected, but the head, voice, tongue, legs, and trunk can also be involved. The frequency of tremors may decrease with age, but their severity may increase. Emotional agitation, stress, fever, physical fatigue, or hypoglycemia can trigger and / or increase the severity of tremors. Symptoms generally develop over a long period, becoming visible after onset and potentially persisting.

[0294] Orthostatic tremor is characterized by rapid (e.g., above 12 Hz) rhythmic muscle contractions in the legs and trunk immediately after standing. The spasms are felt in the thighs and legs, and patients may tremble uncontrollably when asked to stand in one place. Orthostatic tremor can occur in patients with essential tremor.

[0295] Parkinsonian tremors are caused by damage to the brain structures that control movement. Often a precursor to Parkinson's disease, tremors typically manifest as a "pill-rolling" movement of the hand, but can also affect the chin, lips, legs, and trunk. The onset of Parkinsonian tremors typically begins after age 60. The movement may begin in one limb or one side of the body and progress to the other side.

[0296] Physiological tremors can occur in normal individuals and are not clinically significant. They can be seen in all voluntary muscle groups. Physiological tremors can be caused by certain drugs, alcohol withdrawal, or medical conditions including hyperthyroidism and hypoglycemia. These tremors typically have a frequency of approximately 10 Hz.

[0297] Psychogenic tremors or hysterical tremors can occur at rest, during postural movements, or during active movements. Patients with psychogenic tremors may also have conversion disorder or another psychiatric disorder.

[0298] Red nuclear tremor is characterized by slow, coarse tremors that can occur at rest, in posture, and when intentional. This tremor may be associated with conditions affecting the red nucleus in classic, rare strokes of the midbrain.

[0299] Parkinson's disease affects the nerve cells in the brain that produce dopamine. Symptoms include muscle rigidity, tremors, and changes in speech and gait. Tremor paralysis is characterized by tremors, bradykinesia, rigidity, and postural instability. Tremor paralysis shares symptoms with Parkinson's disease, but it is a group of symptoms rather than a progressive neurodegenerative disease.

[0300] Dystonia is a movement disorder characterized by persistent or intermittent muscle contractions that are abnormal and often cause repetitive movements or postures. Dystonic movements can be patterned, twisting, and trembling. Dystonia is often triggered or aggravated by voluntary movement and is often associated with an overflow of muscle activation.

[0301] Chorea is a neurological disorder typically characterized by rhythmic, involuntary movements affecting the shoulders, hips, and face. Huntington's disease is a genetic disorder that weakens nerve cells in the brain. Symptoms include uncontrolled movements, clumsiness, and balance problems. Huntington's disease can interfere with walking, speaking, and swallowing.

[0302] Ataxia refers to the loss of complete control over bodily movements and can affect fingers, hands, arms, legs, body, speech, and eye movements.

[0303] Myoclonus and startle are responses to sudden and unexpected stimuli that may be auditory, tactile, visual, or vestibular.

[0304] Tics are involuntary movements that typically begin suddenly, are short, repetitive but not rhythmic, and often mimic normal behavior, occurring outside the context of normal activity. Tics can be classified as motor tics or vocal tics; motor tics are associated with movement, and vocal tics are associated with sound. Tics can be characterized as simple or complex. For example, simple motor tics involve only a few muscles limited to a specific part of the body. Tourette syndrome is a hereditary neuropsychiatric disorder that begins in childhood and is characterized by multiple motor tics and at least one vocal tic.

[0305] Lower limb restlessness syndrome is a neurological sensorimotor disorder characterized by an irresistible urge to move the legs while at rest.

[0306] Stiff person syndrome is a progressive motor disorder typically characterized by involuntary, painful spasms and muscle rigidity involving the lumbar spine and legs. Typically, it presents with an ankylosing gait accompanied by excessive lumbar lordosis. Characteristic abnormalities are typically observed in EMG recordings of continuous motor unit activity of the paravertebral axial muscles. A variant is "stiff-limb syndrome," which results in localized rigidity, typically affecting the distal legs and feet.

[0307] Gait disorders refer to abnormalities in the manner or style of walking, resulting from neuromuscular, arthritis, or other physical changes. Gaits are classified according to a system of abnormal walking movements and include hemiplegic gait, diplegic gait, neuropathic gait, myopathy gait, Parkinson's disease-like gait, chorea-like gait, ataxic gait, and sensory gait.

[0308] Anesthesia / Sedation Anesthesia is a pharmacologically induced, reversible state characterized by amnesia, analgesia, loss of responsiveness, loss of skeletal muscle reflexes, a reduced stress response, or all of these simultaneously. These effects can be obtained from a single drug that provides the correct combination of effects on its own, or sometimes from a combination of drugs (e.g., hypnotics, sedatives) to achieve a very specific combination of results. Anesthesia can be achieved using a combination of paralyzing and analgesic drugs. Anesthesia allows patients to undergo surgical procedures and other steps without experiencing the difficulties and pain they would otherwise experience.

[0309] Sedation is generally the reduction of nervousness or agitation through the administration of pharmacological agents to facilitate medical or diagnostic procedures.

[0310] Sedation and analgesia encompass a continuum of states of consciousness ranging from minimal sedation (anxiety relief) to general anesthesia.

[0311] Minimal sedation is also known as anxiety relief. Minimal sedation is a drug-induced state in which the patient responds normally to verbal commands. Cognitive function and coordination may be impaired. Ventilation and cardiovascular function are typically unaffected.

[0312] Moderate sedation / analgesia (conscious sedation) is a drug-induced decrease in consciousness in which the patient intentionally responds to verbal commands, either alone or with light tactile stimulation. Typically, intervention to maintain the patient's airway is not required. Spontaneous ventilation is usually adequate. Cardiovascular function is usually maintained.

[0313] Deep sedation / analgesia is a drug-induced decrease in consciousness in which the patient cannot easily awaken but responds intentionally (rather than reflexively withdrawing from painful stimuli) after repeated or painful stimuli. Independent ventilatory function may be impaired, and the patient may require assistance to maintain their airway. Spontaneous ventilation may be insufficient. Cardiovascular function is usually maintained.

[0314] General anesthesia is drug-induced loss of consciousness in which the patient is unable to awaken even in response to painful stimuli. Because the ability to maintain independent ventilatory function is often impaired, assistance to maintain the patient's airway is frequently required. Positive pressure ventilation may be necessary due to reduced spontaneous ventilation or drug-induced neuromuscular dysfunction. Cardiovascular function may be impaired.

[0315] Sedation in the intensive care unit (ICU) allows for a reduced awareness of the patient's environment and decreased response to external stimuli. This can play a role in treating patients with critical illness and encompasses a wide range of symptom control, which varies from patient to patient and individual to individual throughout the course of the patient's illness. Heavy sedation in intensive care is used to facilitate endotracheal tube tolerance and ventilator synchronization (often accompanied by neuromuscular blocking agents).

[0316] In some embodiments, sedation (e.g., prolonged sedation, sustained sedation) is induced in the ICU and maintained over extended periods (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months). Prolonged sedatives may have a long duration of action. Sedatives in the ICU may have a short elimination half-life.

[0317] Sedation and analgesia during a procedure (also known as conscious sedation) is a technique that involves administering sedatives or dissociative agents, with or without analgesics, to enable a subject to tolerate an uncomfortable procedure while maintaining cardiopulmonary function. [Examples]

[0318] For the purpose of allowing a better understanding of the present invention as described herein, the following examples are provided. The synthetic and biological examples described herein refer to the compounds and pharmaceuticals provided herein. These are provided to illustrate the compositions and methods and should not be construed as limiting their scope.

[0319] material and method The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it is understood that other process conditions may also be used unless otherwise stated. Optimal reaction conditions may vary depending on the specific reactants or solvent used, but such conditions can be determined by those skilled in the art through conventional optimization.

[0320] Furthermore, as may be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. The selection of suitable protecting groups for specific functional groups, as well as the conditions suitable for protection and deprotection, are well known in the art. For example, numerous protecting groups and their introduction and removal are described in TW Greene and PGMWuts, *Protecting Groups in Organic Synthesis*, 2nd edition, Wiley, New York, 1991, and the references cited therein.

[0321] The compounds provided herein may be isolated and purified by known standard procedures. Such procedures include, but are not limited to, recrystallization, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following schemes are presented in detail with respect to the preparation of representative oxysterols listed herein. The compounds provided herein may be prepared by those skilled in the art of organic synthesis from known or commercially available starting materials and reagents. Exemplary chiral columns available for use in the separation / purification of enantiomers / diastereomers provided herein include, but are not limited to, CHIRALPAK® AD-10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ, and CHIRALCEL® OK.

[0322] The 1H-NMR reported herein (e.g., for the region between approximately 0.5 and 4 ppm of δ(ppm)) is understood to be an exemplary interpretation (e.g., an exemplary peak integral) of the NMR spectrum of the compound.

[0323] LC-ELSD / MS: (Mobile phase: 1.5 ml / 4 L water containing TFA (solvent A) and 0.75 ml / 4 L acetonitrile containing TFA (solvent B), elution gradient 30%-90% (solvent B) for 0.9 minutes and retention at 90% for 0.6 minutes at a flow rate of 1.2 ml / min; Column: Xtimate C18 2.1 × 30 mm, 3 μm; Wavelength: UV 220 nm; Column temperature: 50 °C; MS ionization: ESI; Detector: PDA & ELSD.

[0324] Abbreviations: CAN: Acetonitrile; PE: Petroleum ether; DCM: Dichloromethane; Depositphotos: Ethyl acetate; EDCI: N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride. intermediate INT3 synthesis procedure [ka] INT2 synthesis To a solution of 3,6-dibromo-2-methylpyridine (1.0 g, 3.98 mmol) in toluene (50 mL) at -70°C, n-BuLi (2.5 M in hexane, 1.90 mL, 4.77 mmol) was slowly added. After stirring at -70°C for 2 hours, tributyl(chloro)stannane (1.68 g, 5.17 mmol) was added. After stirring at -70°C for 1 hour, the reaction mixture was heated to -10°C and saturated NH4Cl aqueous solution (10 mL) was added. The mixture was extracted with ethyl acetate (2 × 50 mL), the combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by flash column chromatography (PE) to obtain INT2 (1.61 g, 88%) as an oily substance. 1 H NMR (400 MHz, CDCl3) δ 7.63-7.56 (m, 1H), 7.11-7.03 (m, 1H), 2.66 (s, 3H), 1.63-1.43 (m, 5H), 1.36-1.29 (m, 6H), 1.12-1.05 (m, 4H), 0.93-0.85 (m, 12H). INT3 synthesis To a suspension of INT2 (1.3 g, 2.81 mmol) in xylene (15 mL), 2-bromo-5-fluoropyrimidine (470 mg, 2.66 mmol), Pd(PPh3)2Cl2 (100 mg, 0.1424 mmol), and PPh3 (75 mg, 0.2859 mmol) were added under N2 conditions. After stirring at 135°C for 16 hours, the reaction mixture was quenched with water (50 mL) and extracted with DCM (2 × 50 mL). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by flash column chromatography (ethyl acetate in PE, 15%) to obtain INT3 (400 mg, 53%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 8.76 (s, 2H), 8.17 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 2.83 (s, 3H); 19 F NMR (376 MHz, CDCl3) δ -137.524. Combination of INT4 and INT5 [ka] A suspension of 3,6-dibromo-2-methylpyridine (1.5 g, 5.97 mmol), 3-methyl-1H-pyrazole (977 mg, 11.9 mmol), and TMEDA (1.38 g, 11.9 mmol) in DMSO (30 mL) was prepared by adding K2CO3 (2.47 g, 17.9 mmol) under N2 conditions. The suspension was degassed under reduced pressure and purged with N2 three times. Then, CuI (1.13 g, 5.97 mmol) was added to the suspension, and the suspension was degassed under reduced pressure and purged with N2 three times. The mixture was first stirred at 20°C for 30 minutes, then heated at 90°C for 12 hours, after which the reaction mixture was diluted with water (50 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL), and the combined organic solution was diluted with water. The residue was washed with (50 mL) and brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column (PE) to obtain a solid (1.5 g), which was further purified by SFC (column: Chiralpak AD-3 150 × 4.6 mm ID, 3 μm; mobile phase: A: CO2 B: ethanol (0.05% DEA); gradient: 5 minutes on B from 5% to 40%, then 2.5 minutes at 40%, followed by 2.5 minutes holding on 5% B; flow rate: 2.5 mL / min) to obtain both INT5 (384 mg, 26%, peak 1) and INT4 (106 mg, 7%, peak 2) as solids. The structures were confirmed by 2D NMR. INT5: 1 H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 1.2 Hz, 1H), 6.18 (s, 1H), 2.68 (s, 3H), 2.65 (s, 3H). Example 1: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17S)-3-(ethoxymethyl)-3-hydroxy-13-methyl-N-(pyridine-4-yl)hexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide (A2) [ka] General method 1: To a mixture of A1 (100 mg, 0.274 mmol, reported in WO2018013613) in pyridine (5 mL), EDCI (57.4 mg, 0.301 mmol) was added. After stirring at room temperature for 15 minutes, pyridine-4-amine (28.3 mg, 0.301 mmol) was added to the mixture. After stirring at 60 °C for 16 hours, the reaction mixture was quenched with HCl (1 M, 10 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic solution was washed with brine (5 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by preparative HPLC (column: Xbridge 150×30mm×10um, conditions: water (0.05% aqueous ammonia v / v)-ACN, start B: 60%, end B: 90%, gradient time: 7 min, flow rate: 25 ml / min) to obtain A2 (29 mg, 24%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 8.55-8.45 (m, 2H), 7.55-7.45 (m, 2H), 7.20-7.15 (s, 1H), 3.60-3.40 (m, 4H), 2.80-2.75 (m, 1H), 2.40-2.25 (m, 2H), 2.00-1.95 (m, 1H), 1.85-1.55 (m, 9H), 1.50-1.00 (s, 15H), 0.74 (s, 3H); LC-ELSD / MS purity 99%, C 27 H 41 N2O3[M+H] + The MS ESI calculated value is 441, and the measured value is also 441. Example 2: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17S)-3-(ethoxymethyl)-3-hydroxy-13-methyl-N-(3-methylpyridine-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide (A4) [ka] General Method 2: AgOTf (56.0 mg, 0.218 mmol) and 3-methylpyridine-2-amine (70.7 mg, 0.654 mmol) were added to a solution of A3 (200 mg, 0.436 mmol, as reported in WO2018013613) in DCM (3 mL). After stirring at room temperature for 16 hours, the reaction mixture was filtered, and the filter cake was washed with DCM (3 × 3 mL). The combined organic solution was washed with 1 M HCl (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was subjected to HPLC (column: Waters Xbridge 150 × 25 5u, conditions: water (10 mM NH4HCO3)-ACN, start B 57, end B 77, gradient time (min) 6). Purification was performed using 100% B (retention time (min) 2, flow rate (ml / min) 25) to obtain A4 (9 mg, 5%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 8.26-8.22 (m, 1H), 7.58-7.52 (m, 1H), 7.35-7.31 (m, 1H), 7.12-7.06 (m, 1H), 3.60-3.50 (m, 2H), 3.48-3.38 (m, 2H), 2.71 (s, 1H), 2.46-2.38 (m, 1H), 2.31-2.10 (m, 5H), 1.90-1.56 (m, 8H), 1.56-1.05 (m, 16H), 0.81 (s, 3H); LC-ELSD / MS 100% purity, C 28 H 43 N2O3[M+H] + The MS ESI calculated value is 455, and the measured value is also 455. Example 3: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17S)-3-(ethoxymethyl)-3-hydroxy-13-methyl-N-(3-(trifluoromethyl)pyridine-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide (A5) [ka] General method 3: Oxalyl dichloride (76.4 mg, 0.602 mmol) and DMF (2 mg, 0.0274 mmol) were successively added to a solution of A1 (200 mg, 0.548 mmol) in anhydrous DCM (2 mL) at room temperature. After stirring for 1 hour, 3-(trifluoromethyl)pyridine-2-amine (133 mg, 0.822 mmol) and DIPEA (352 mg, 2.73 mmol) were added. After 16 hours at room temperature, the reaction mixture was quenched with water (2 mL) and extracted with DCM (2 × 2 mL). The combined organic solution was concentrated, The product (80 mg) was purified by preparative HPLC (column: YMC-Actus Triart C18 100 × 30 mm × 5 μm; conditions: water (0.05% HCl)-ACN; gradient: 60%~90% B; flow rate: 25 mL / min), and lyophilized. The solid was dissolved in DCM (10 mL), washed with saturated NaHCO3 (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and dried in a vacuum dryer at 70°C for 24 hours to obtain A5 (41 mg, 15%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 8.68 (d, J = 4.0 Hz, 1H), 7.98-7.92 (m, 1H), 7.53 (s, 1H), 7.24-7.20 (m, 1H), 3.57-3.50 (m, 2H), 3.47-3.38 (m, 2H), 2.72 (s, 1H), 2.52-2.43 (m, 1H), 2.36-2.25 (m, 1H), 2.11-2.03 (m, 1H), 1.90-1.70 (m, 6H), 1.68-1.59 (m, 2H), 1.51-1.34 (m, 7H), 1.29-1.09 (m, 9H), 0.80 (s, 3H); 19 F NMR (400 MHz, CDCl3) δ -61.82; LC-ELSD / MS purity 99%, C 28 H 40 F3N2O3[M+H] + The MS ESI calculated value is 509, and the measured value is also 509. Example 4: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17S)-3-(ethoxymethyl)-3-hydroxy-13-methyl-N-(6-methylpyridine-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide (A8) A7 synthesis [ka] To a solution of A1 (2.00 g, 5.48 mmol, reported in WO2018013613) in DMF (20 mL), HATU (1.98 g, 8.22 mmol) and DIPEA (5.66 g, 43.8 mmol) were added. After stirring at room temperature for 15 minutes, NH4Cl (1.17 g, 21.9 mmol) was added. After stirring for 16 hours, the reaction mixture was diluted with dimethyl alcohol (50 mL), washed with water (50 mL), 3% aqueous LiCl solution (50 mL), water (50 mL), and brine (50 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash column (0-10% DCM in CH3OH) to obtain A7 (2.0 g, 100%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 5.47-5.03 (m, 2H), 3.53 (q, J=7.0 Hz, 2H), 3.42 (q, J=9.2 Hz, 2H), 2.25-2.05 (m, 2H), 1.99-1.92 (m, 1H), 1.85-1.34 (m, 14H), 1.34-1.00 (m, 11H), 0.71 (s, 3H). A8 synthesis [ka] General method 4: Pd2(dba)3 (50.3 mg, 0.055 mmol) was added to a mixture of 2-chloro-6-methylpyridine (105 mg, 0.824 mmol), A7 (200 mg, 0.550 mmol), xanthophos (31.8 mg, 0.055 mmol), and cesium carbonate (355 mg, 1.09 mmol) in dioxane (5 mL) that had been sprayed with nitrogen for 2 minutes. After heating in a microwave at 105°C for 1 hour, the reaction product was filtered, concentrated, and purified by preparative HPLC (column: Xtimate C18 150×25mm×5um; conditions: water (0.225% FA)-ACN, start B 60; end B 90, gradient time (min) 8; 100% B, retention time (min) 2; flow rate (ml / min) 30) to obtain A8 (43 mg, 17%) as a solid. 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=7.8 Hz, 1H), 7.67 (br s, 1H), 7.57 (t, J=7.8 Hz, 1H), 6.87 (d, J=7.4 Hz, 1H), 3.53 (q, J=6.9 Hz, 2H), 3.47-3.39 (m, 2H), 2.73 (s, 1H), 2.44 (s, 3H), 2.36-2.22 (m, 2H), 2.05 (br d, J=11.8 Hz, 1H), 1.88-1.56 (m, 6H), 1.56-1.30 (m, 9H), 1.30-1.00 (m, 9H), 0.74 (s, 3H); LC-ELSD / MS purity 99%, C 28 H 43 N2O3[M+H] + The MS ESI calculated value is 455, and the measured value is also 455. Example 5: Synthesis of (3R,5S,8R,9S,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-10,13-dimethyl-N-(6-methylpyridine-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide (A13) Synthesis of A11 [ka] Liquid bromine (2.63 g, 16.5 mmol) was slowly added at 0°C to a vigorously stirred aqueous sodium hydroxide solution (18.3 mL, 3 M, 55.1 mmol). When the bromine dissolved, the mixture was diluted with cold dioxane (10 mL), and then dioxane (25 mL) of A10 (2.0 g, 5.51 mmol, reported in WO2016061527) and The reaction was slowly added to a stirred solution in water (10 mL). The homogeneous solution slowly became colorless, and a precipitate formed. After stirring at room temperature for 16 hours, the reaction was quenched with an aqueous solution of Na₂SO₃ (30 mL), and the pH was adjusted with hydrochloride acid (3N), which produced a precipitate. The suspension was dissolved in RINKAN (50 mL), and the organic phase was recovered. The aqueous phase was extracted with RINKAN (2 × 50 mL). The combined organic matter was washed with saturated brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain A11 (2.0 g) as a solid. Synthesis of A12 [ka] To a solution of A11 (750 mg, 2.05 mmol) in DMF (10 mL), HATU (990 mg, 4.11 mmol) and DIPEA (2.11 g, 16.4 mmol) were added. After stirring at room temperature for 15 minutes, NH4Cl (438 mg, 8.20 mmol) was added. After stirring for 16 hours, the reaction mixture was diluted with  (50 mL), washed with water (50 mL), 3% LiCl aqueous solution (50 mL), water (50 mL), and brine (50 mL), dried over sodium sulfate, filtered, concentrated, and purified by flash column (0-50% DCM in CH3OH) to obtain A12 (530 mg, 71%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 5.31-5.20 (m, 2H), 3.38 (s, 3H), 3.18 (s, 2H), 2.22-1.95 (m, 4H), 1.78-1.56 (m, 4H), 1.56-0.78 (m, 16H), 0.76 (s, 3H), 0.71 (s, 3H). LC-ELSD / MS 99% purity, C22 H 38 NO3[M +H] + The MS ESI calculated value is 364, and the measured value is also 364. Synthesis of A13 [ka] General method 5: A mixture of 2-chloro-6-methylpyridine (105 mg, 0.824 mmol), A12 (200 mg, 0.550 mmol), xanthophos (31.8 mg, 0.055 mmol), and cesium carbonate (357 mg, 1.09 mmol) in dioxane (3 mL) was sprayed with nitrogen for 2 minutes, and then Pd2(dba)3 (50.3 mg, 0.055 mmol) was added. After heating in a microwave at 130°C for 1 hour, the reaction mixture was filtered and purified by preparative HPLC (column: Xtimate C18 150×25mm×5um; conditions: water (0.225% FA)-ACN, start B 80, end B 100, gradient time (min) 7; 100% B, retention time (min) 2, flow rate (ml / min) 25) to obtain A13 (137 mg, 55%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 8.03 (d, J=8.3 Hz, 1H), 7.70 (s, 1H), 7.56 (t, J=7.8H z, 1H), 6.86 (d, J=7.5 Hz, 1H), 3.38 (s, 3H), 3.18 (s, 2H), 2.43 (s, 3H), 2.35- 2.23 (m, 2H), 2.04 (br d, J=11.3 Hz, 2H), 1.85-1.56 (m, 3H), 1.56-1.10 (m, 15H), 1.05-0.80 (m, 2H), 0.75 (s, 3H), 0.73 (s, 3H). LC-ELSD / MS purity 99%, C 28 H 43 N2O3[M+H] + The MS ESI calculated value is 455, and the measured value is also 455. Example 6: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethyl-N-(2-methylimidazo[1,2-a]pyridine-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide [ka] (3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxylic acid (100 mg, 0.312 mmol) was dissolved in pyridine (2 mL), to which EDCI (71.7 mg, 0.374 mmol) and 2-methylimidazo[1,2-a]pyridine-3-amine (45.9 mg, 0.312 mmol) were added at 25°C. After stirring at 25°C for 16 hours, the reaction mixture was quenched with water (10 mL) and extracted with ELISA (2 × 20 mL). The combined organic solution was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the product. This product was purified by preparative HPLC (column: YMC-Actus Triart C18 100×30mm×5um, gradient: 10-80%B (A=0.05%HCl-ACN, B=acetonitrile), flow rate: 25mL / min) to obtain A14 (75mg, 63%) as a solid. 1 1H NMR (400 MHz, MeOD) δ 7.90 (d, J=6.8 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.35-7.27 (m, 1H), 6.97-6.93 (m, 1H), 2.62 (t, J=9.4 Hz, 1H), 2.33 (s, 3H), 2.30-2.08 (m, 2H), 2.00-1.65 (m, 8H), 1.64-1.31 (m, 10H), 1.28-1.10 (m, 8H), 0.83 (s, 3H); LC-ELSD / MS purity 99%, C 28 H 40 N3O2[M+H] + The MS ESI calculated value is 450, and the measured value is also 450. Example 7: Synthesis of (3R,5S,8R,9R,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-13-methyl-N-(6-methylpyridine-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide (A18) Synthesis of A16 [ka] Liquid bromine (1.5 g, 9.43 mmol) was slowly added at 0°C to a vigorously stirred aqueous sodium hydroxide solution (1.48 g NaOH, 37.1 mmol, 2.5 M). After stirring at room temperature for 30 minutes, the mixture was slowly added to a stirred solution of A15 (1.0 g, 2.86 mmol, reported in WO2013056181) in dioxane (10 mL). A homogeneous solution slowly became colorless, and a precipitate formed. After stirring for 16 hours, the reactants were quenched with an aqueous Na2SO3 solution (50 mL), and the pH was adjusted with an aqueous HCl solution to the pH at which a precipitate was obtained (approximately 6). The solid was filtered and washed with water (3 × 20 mL) to obtain a solid, which was dried under reduced pressure to obtain A16 (1.0 g) as a solid. 1 H NMR (400 MHz, CDCl3) δ 11.89 (s, 1H), 4.01 (s, 1H), 3.23 (s, 3H), 3.04 (s, 2H), 2.26 (m, 1H), 1.90 (m, 2H), 1.71 (m, 5H), 1.45 (m, 2H), 1.13 (m, 12H), 0.61 (s, 5H). Synthesis of A17 [ka] A solution of A16 (500 mg, 1.42 mmol), HATU (809 mg, 2.13 mmol), and NH4Cl (151 mg, 2.84 mmol) in DMF (5 mL) at room temperature was mixed with DIPEA (549 mg, 4.26 mmol). After stirring for 18 hours, the mixture was poured into water (20 mL) and extracted with SiO2 (3 × 20 mL). The combined organic solution was washed with brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The product was purified by preparative HPLC separation (column: YMC-Actus Triart C18 100×30mm×5um), gradient: 65-95%B (A=water (0.05%HCl), B=ACN), flow rate: 25mL / min) to obtain A17 (600mg) as a solid. This was then ground with 10mL of MeOH and 10mL of water to obtain A17 (330mg, 55%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 6.86 (s, 1H), 6.70 (s, 1H), 4.01 (s, 1H), 3.23 (s, 3H), 3.04 (s, 2H), 2.11 (m, 1H), 1.97 (m, 1H), 1.74 (m, 2H), 1.57 (m, 6H), 1.32 (m, 4H), 1.03 (m, 8H), 0.57 (m, 5H). A18 synthesis [ka] General method 7: To a suspension of A17 (300 mg, 0.858 mmol) and 2-chloro-6-methylpyridine (218 mg, 1.71 mmol) in anhydrous dioxane (4 mL), Pd2(dba)3 (78.5 mg, 0.0858 mmol), xanthophos (49.6 mg, 0.0858 mmol), and Cs2CO3 (557 mg, 1.71 mmol) was added. After heating in a microwave at 130°C for 1 hour, the mixture was poured into water (10 mL) and extracted with butyl (3 × 10 mL). The combined organic solution was washed with brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column (30% butyl in PE) to obtain A18 (200 mg) as a solid. The solid was ground with n-hexane (10 mL) at room temperature to obtain A18 (167 mg) as a solid. 1 H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.4 Hz, 1H), 7.64 (s, 1H), 7.56 (t, J = 7.6 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 3.38 (s, 3H), 3.18 (s, 2H), 2.43 (s, 3H), 2.30 (m, 2H), 2.02 (m, 2H), 1.76 (m, 6H), 1.57 (m, 8 H), 1.21 (m, 5H), 0.74 (m, 5H). LC-ELSD / MS purity 99%, C 34 H 48 N2O3[M+H] + The MS ESI calculated value is 441, and the measured value is also 441. Example 8: Synthesis of (3R,5R,8S,9S,10S,13S,14S,17S)-N-(1,3-dimethyl-1H-pyrazole-5-yl)-3-(ethoxymethyl)-10-ethyl-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide (29) [ka] A20 synthesis To a suspension of PPh3MeBr (548g, 1536mmol) in THF (1L), t-BuOK (172g, 1536mmol) was added at room temperature. After stirring at 45°C for 1 hour, A19 (200g, 512mmol, as reported in WO2016 / 134301) was added. A solution of ) in THF (500 mL) was added. After stirring at 45°C for 10 minutes, saturated NH4Cl solution (500 mL) and ethyl acetate (500 mL) were added to the mixture. The organic solution was separated, and the aqueous layer was extracted with ethyl acetate (2 × 300 mL). The combined organic solution was washed with brine (2 × 300 mL), dried over anhydrous Na2SO4, filtered, concentrated, ground in MeOH / H2O (1 L / 1 L) at 15°C, and purified by silica gel chromatography (PE / ethyl acetate = 50 / 1 to 20 / 1) to obtain A20 (137 g, 69%) as an oily substance. 1 1H NMR (400 MHz, CDCl3) δ 6.40-6.25 (m, 1H), 5.15-5.00 (m, 2H), 3.95-3.75 (m, 9H),2.10-1.65 (m, 9H), 1.65-1.25 (m, 5H), 1.25-1.05 (m, 6H),0.85-0.75 (m, 4H). A21 synthesis To a solution of A20 (70 g, 180 mmol) in THF (1 L), Pd / C (dry form, 10% supported on carbon, 10 g) was added under N2 conditions. The suspension was degassed under reduced pressure and purged with H2 three times. After hydrogenation at 30 psi at room temperature for 16 hours, the reaction mixture was filtered through a Celite pad and washed with THF (3 × 500 mL). The filtrate was concentrated to obtain A21 (141 g, derived from a combination of two parallel reactions) as an oily substance. 1 1H NMR (400 MHz, CDCl3) δ H 3.95-3.75 (m, 9H), 2.10-1.90 (m, 2H), 1.90-1.65 (m, 8H), 1.65-1.25 (m, 4H), 1.25-1.05 (m, 8H), 0.80-0.45 (s, 7H). Synthesis of A22 A solution of A21 (141 g, 361 mmol) in THF (1000 mL) was mixed with aqueous HCl (361 mL, 4 M, 1444 mmol). After stirring at room temperature for 16 hours, the mixture was poured into water (500 mL). The organic phase was collected, and the aqueous layer was extracted with SiO2 (2 × 300 mL). The combined organic solution was washed with saturated aqueous NaHCO3 (500 mL), H2O (2 × 300 mL), and brine (200 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and ground on PE (300 mL) to obtain A22 (82 g, 73%) as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 2.80-2.70 (m, 1H),2.55-2.45 (m, 3H),2.45-2.15 (m, 1H), 2.15-2.00 (m, 3H), 2.00-1.90 (m, 1H), 1.90-1.65 (m, 6H), 1.65-1.30 (m, 2H), 1.30-1.10 (m, 7H),0.88 (s, 3H),1.85-0.75 (m, 3H). A23 synthesis To a stirred solution of trimethylsulfonium iodide (22.2 g, 109 mmol) in DMSO / THF (100 mL / 500 mL), NaH (4.35 g, 109 mmol, 60% in oil) was added at 0°C. After 1 hour, the mixture was added to a solution of A23 (30 g, 99.1 mmol) in DMSO (100 mL). After stirring at room temperature for 4 hours, the reaction product was diluted with water (200 mL) and extracted with siRNA (2 × 100 mL). The combined organic solution was washed with water (2 × 100 mL) and brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain A23 (35 g) as an oil. Synthesis of A24 and A24a Na (25.4 g, 1107 mmol) was added to anhydrous EtOH (200 mL) in 10 divided portions at 15 °C. After stirring at 75 °C for 1 hour, a solution of A23 (22 g, 69.5 mmol) in anhydrous ethanol (50 mL) was added. After stirring at 75 °C for 16 hours, the reaction mixture was diluted with water (500 mL), concentrated, and most of the solvent was removed. The mixture was extracted with ELISA (2 × 200 mL), and the combined organic solution was diluted with saturated brine (2 × 100 mL). The residue was washed, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column (0-20% phenylethylamine in PE) to obtain A24 (12 g) as oil and A24a (7 g) as solid. A24: 1 1H NMR (400 MHz, CDCl3) δ H 3.60-3.45 (m, 2H),3.45-3.30 (m, 2H),2.45-2.30 (m, 1H),2.10-1.90 (m, 4H), 1.90-1.55 (m, 5H), 1.55-1.30 (m, 7H), 1.30-1.10 (m, 11H), 0.90-0.80 (m, 3H), 0.80-0.60 (m, 3H).A24a: 1 1H NMR (400 MHz, CDCl3) δ H 3.55-3.46 (m, 2H), 3.25-3.15 (m, 2H),2.47-2.35 (m, 1H),2.10-1.95 (m, 4H), 1.95-1.85 (m, 1H), 1.85-1.60 (m, 5H), 1.55-1.35 (m, 6H), 1.35-1.15 (m, 11H), 0.90-0.80 (m, 6H) A24 synthesis To a suspension of bromo(ethyl)triphenylphosphoran (48.9 g, 132 mmol) in THF (200 mL), t-BuOK (14.7 g, 132 mmol) was added under N2 conditions at room temperature. After stirring at 45 °C for 1 hour, a solution of A24 (12 g, 33.0 mmol) in THF (20 mL) was added. After stirring at 45 °C for 16 hours, the mixture was treated with NH4Cl (100 mL) and the organic solution was recovered. The aqueous phase was extracted with ELISA (2 × 50 mL), the combined organic solution was washed with brine (2 × 40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was ground in MeOH / H2O (50 mL / 50 mL) at room temperature to obtain A25 (17 g) as an oily substance. A26 synthesis To a solution of A25 (17g, 45.3 mmol) in THF (100 mL), 9-BBN dimer (22.1g, 90.6 mmol) was added at room temperature. After stirring for 16 hours, the reaction mixture was cooled to 0°C, and ethanol (20.8g, 453 mmol) and NaOH (90.6 mL, 5M, 453 mmol) were added very slowly. After the addition was complete, H2O2 (45.3 mL, 453 mmol, 30%) was slowly added, and the internal temperature was maintained below 15°C. The resulting solution was stirred at 75°C for 1 hour. A saturated aqueous solution of Na2S2O3 (100 mL) was added, and the mixture was stirred at 0°C for 1 hour, after which the mixture was added to water (2 L). The mixture was extracted with dimethyl (2 × 200 mL), the combined organic solution was washed with brine (50 mL), dried over anhydrous sodium 2 SO4, filtered, and concentrated under reduced pressure to obtain A26 (18 g) as an oil. A27 synthesis To a solution of A26 (18 g, 45.8 mmol) in DCM (200 mL), PCC (19.6 g, 91.6 mmol) and silica gel (15 g) were added at room temperature. After stirring for 3 hours, the reaction mixture was filtered, and the residue was washed with anhydrous DCM (2 × 100 mL). The combined organic solution was concentrated and purified by flash column (PE with 0-20% ethyl phosphate) to obtain A27 (8 g, 45%) as a solid. 1 1H NMR (400 MHz, CDCl3) δ H3.60-3.50 (m, 2H), 3.50-3.30 (m, 2H),2.74 (s, 1H), 2.60-2.45 (m, 1H),2.20-2.05 (m, 4H),2.05-1.75 (m, 2H), 1.75-1.50 (m, 7H), 1.50-1.30 (m, 7H), 1.30-1.05 (m, 10H), 0.80-0.65 (m, 3H), 0.59 (s, 3H); LC-ELSD / MS purity 99%, C 25 H 41 O2[M+H-H2O] + The MS ESI calculated value is 373, and the measured value is also 373. A28 synthesis Liquid bromine (7.15 g, 44.8 mmol) was slowly added at 0°C to a vigorously stirred aqueous sodium hydroxide solution (35.6 mL, 3 M, 107 mmol). Occasionally, the mixture was diluted with cold dioxane (10 mL) and slowly added to a stirred solution of A27 (3.5 g, 8.9 mmol) in dioxane (30 mL) and water (15 mL). After stirring at room temperature for 16 hours, the reaction was quenched with aqueous Na2SO3 solution (30 mL), and then the mixture was heated at 80°C until the solid material dissolved. The solution was acidified to approximately pH 6 with hydrochloride acid (3N) to obtain a precipitate. The precipitated solid was filtered off, washed with water (2 × 50 mL), and dried to obtain A28 (3.8 g) as a solid. 1 1H NMR (400 MHz, CDCl3)δ H 3.65-3.50 (m, 2H), 3.50-3.30 (m, 2H), 2.45-2.30 (m, 1H), 2.15-2.00 (m, 2H), 2.00-1.80 (m, 1H), 1.80-1.50 (m, 8H), 1.50-1.25 (m, 7H), 1.25-1.05 (m, 11H), 0.90-0.75 (m, 3H), 0.71 (s, 3H); LC-ELSD / MS purity 99%, C 24 H 40 O4Na [M+Na]+ The MS ESI calculated value is 415, and the measured value is also 415. A29 synthesis General method 8: To a solution of A28 (200 mg, 0.5094 mmol) in pyridine (5 mL), EDCI (389 mg, 2.03 mmol) was added. After stirring at room temperature for 10 minutes, 1,3-dimethyl-1H-pyrazole-5-amine (67.9 mg, 0.6112 mmol) was added. After stirring for 16 hours, water (20 mL) and ethyl acetate (20 mL) were added to the reaction mixture. The organic solution was separated. The aqueous phase was extracted with ethyl acetate (2 × 10 mL). The combined organic solution was washed with brine (2 × 10 mL), dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by HPLC (column: YMC-Actus Triart C18 100 × 30 mm × 5 μm, gradient: 75-92%B (A = water (0.05% HCl), B = MeCN), flow rate: 25 mL / min) to obtain A29 (150 mg) as a solid. The solid (150 mg) was dissolved in Depositphotos (20 mL) and treated with saturated NaHCO₃ solution (10 mL). After stirring for 30 minutes, the organic phase was separated. The aqueous phase was extracted with Depositphotos (3 × 10 mL). The combined organic solution was washed with saturated brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain A29 (43 mg, 29%) as a solid. 1 1H NMR (400 MHz, CDCl3) δ 6.71 (s, 1H), 6.00 (s, 1H), 3.67 (s, 3H),3.65-3.50 (m, 2H), 3.50-3.30 (m, 2H), 2.76 (s, 1H), 2.35-2.15 (m, 5H), 2.00-1.50 (m, 8H),1.50-1.25 (m, 9H), 1.25-1.05 (m, 9H), 0.90-0.75 (m, 3H), 0.73 (s, 3H); LC-ELSD / MS purity 99%, C 29 H 48 N3O3[M+H] + The MS ESI calculated value is 486, and the measured value is also 486. Example 9: Synthesis of (3R,5R,8S,9S,10R,13S,14S,17S)-N-(5-cyanopyridine-2-yl)-3-(ethoxymethyl)-3-hydroxy-10-(isopropoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide (A38) [ka] Combination of A31 and A32 To a solution of A30 (10 g, 25.4 mmol, reported in WO2016 / 134301) in THF (100 mL) under nitrogen at 0°C, sodium hydride (3.03 g, 76.1 mmol, w / w, 60%) was added, followed by dropwise addition of THF (50 mL) containing diisopropyl sulfate (32.6 g, 177 mmol). The mixture was slowly heated to 20°C, then heated to 60°C. After stirring at 60°C for 72 hours, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic solution was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by flash column chromatography (ethyl acetate in PE, 20%) to obtain a mixture of A31 and A32 (5.2 g) as a solid. A32 synthesis To a solution of A31 (5.2 g, mixture with A32) in THF (80 mL), HCl (4 M, 9 mL, 36.0 mmol) was added at room temperature. After stirring for 16 hours, the reaction product was extracted with ethyl acetate (3 × 80 mL). The combined organic solution was washed with saturated NaHCO3 aqueous solution (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain A32 (3 g, 73%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 3.55 (d, J = 9.2 Hz, 1H), 3.41 (td, J = 6.0, 12.0 Hz, 1H), 3.29 (d, J = 9.2 Hz, 1H), 2.60-2.50 (m, 1H), 2.40 (dd, J = 8.4, 19.2 Hz, 1H), 2.35-2.28 (m, 1H), 2.25-2.17 (m, 2H), 2.09-2.02 (m, 1H), 2.02-1.74 (m, 7H), 1.70-1.08 (m, 9H), 1.06 (dd, J = 1.6, 6.0 Hz, 6H), 0.83 (s, 3H). A33 composite To a stirred solution of trimethylsulfonium iodide (1.53 g, 7.50 mmol) in DMSO (10 mL) and THF (10 mL), NaH (283 mg, 7.12 mmol, 60% in oil) was added at 0°C under N2 for 1 hour. To the mixture, a solution of A32 (2 g, 5.77 mmol) in DMSO (10 mL) was added at 0°C. After stirring at room temperature for 16 hours, the reaction product was diluted with water (150 mL) and extracted with SiO2 (3 × 100 mL). The combined organic solution was washed with water (2 × 100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was combined with another batch prepared from 1.9 g of A32. The combined residue was purified by flash column chromatography (12% ethyl acetate in PE) to obtain A33 (3.9 g) as an oil. A34 composite EtONa (11.0 g, 162 mmol) was added to a solution of A33 (3.9 g, 10.8 mmol) in ethanol (150 mL) at room temperature. After stirring at 78 °C for 16 hours, the reaction mixture was quenched with saturated NH4Cl aqueous solution (100 mL) and extracted with dimethyl phosphate (3 × 100 mL). The combined organic solution was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain both A34 (1 g, 23%) and A34a (910 mg, 21%) as oily substances. A34: 1 H NMR (400 MHz, CDCl3) δ 3.60-3.39 (m, 5H), 3.24-3.18 (m, 1H), 2.71 (s, 1H), 2.43 (dd, J = 8.4, 19.2 Hz, 1H), 2.16-2.07 (m, 1H), 1.99-1.62 (m, 9H), 1.20 (t, J = 6.8 Hz, 14H), 1.13 (d, J = 6.0 Hz, 7H), 0.85 (s, 3H). A35 and A36 combined To a solution of t-BuOK (3.29 g, 29.4 mmol) in t-BuOH (8 mL) under N2 conditions, DME (5 mL) containing A34 (600 mg, 1.47 mmol) was added at room temperature. After stirring for 30 minutes, DME (3 mL) containing TosMic (1.14 g, 5.88 mmol) was added. After stirring at room temperature for 16 hours, the residue was poured into ice water (100 mL) and extracted with  (3 × 80 mL). The combined organic solution was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (ethyl acetate in PE, 12%) to obtain A35 (250 mg, 41%) and A36 (80 mg, 13%) as solids. A35: 1 H NMR (400 MHz, CDCl3) δ 3.61-3.37 (m, 6H), 3.20 (d, J = 9.2 Hz, 1H), 2.77-2.64 (m, 1H), 2.32-2.23 (m, 1H), 2.19-2.05 (m, 1H), 1.99-1.70 (m, 6H), 1.67-1.24 (m, LC-ELSD / MS purity 99%, C 26 H 43 NO3Na [M+Na] + The MS ESI calculated value is 440, and the measured value is also 440. A36: 1 H NMR (400 MHz, CDCl3) δ 3.57-3.38 (m, 6H), 3.20 (d, J = 9.2 Hz, 1H), 2.64 (s, 1H), 2.55 (dd, J = 2.0, 9.2 Hz, 1H), 2.23-2.11 (m, 1H), 2.06-1.93 (m, 1H), 1.91-1.23 (m, 19H), 1.20 (t, J = 6.8 Hz, 4H), 1.12 (d, J = 6.0 Hz, 6H), 0.79 (s, 3H); LC-ELSD / MS purity 97%, C 21 H 31 N [M-iPrOH-EtOH-H2O+H] + The MS ESI calculated value is 296, and the measured value is also 296. A37 synthesis To a solution of A35 (230 mg, 0.5507 mmol) in THF (5 mL), NaOH solution (2.3 g in glycol / H2O (8 mL / 2 mL)) was added. The mixture was evaporated under reduced pressure to remove THF. After stirring at 160 °C for 3 hours, additional KOH (1.54 g, 27.5 mmol) and H2O2 (0.33 mL, 10 M, 3.30 mmol) were added. After further stirring at 160 °C for 3 hours, the reaction mixture was cooled and poured into HCl (1.0 M, 150 mL) to form a precipitate. This precipitate was filtered and washed with water (3 × 50 mL) to obtain a solid. This solid was purified by flash column chromatography (ethyl acetate in PE / DCM (1:1), 60%) to obtain A37 (70 mg, 29%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 5.37 (s, 1H), 5.24 (s, 1H), 3.59-3.35 (m, 5H), 3.20 (d, J = 9.2 Hz, 1H), 2.22-2.09 (m, 1H), 1.98-1.66 (m, 6H), 1.64-1.37 (m, 13H), 1.2 1 (t, J = 7.2 Hz, 8H), 1.12 (d, J = 6.0 Hz, 6H), 0.70 (s, 3H). A38 composite General method 9: A mixture of A37 (70 mg, 0.1606 mmol), 6-chloropyridine-3-carbonitrile (75 mg, 0.4851 mmol), Cs2CO3 (105 mg, 0.3212 mmol), Pd2(dba)3 (30 mg, 0.03278 mmol), and xanthophos (20 mg, 0.03460 mmol) in dioxane (3 mL) was stirred in microwave at 130°C for 1.5 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The solid was purified by flash column chromatography (ethyl acetate in PE, 15%), followed by preparative HPLC (YMC-Actus Triart C18 100×30mm×5um; water (0.05% HCl)-ACN, 70%-100% for 11 minutes; flow rate: 25 mL / min) to obtain A38 (15 mg, 17%) as a solid. 1 H NMR (400 MHz, CDCl3) δ8.53 (d, J = 1.6 Hz, 1H), 8.37 (d, J = 9.2 Hz, 1H), 7.95-7.88 (m, 2H), 3.58-3.50 (m, 3H), 3.49-3.38 (m, 3H), 3.21 (d, J = 9.2 Hz, 1H), 2.39-2.32 (m, 1H), 2.31-2.18 (m, 1H), 2.00 (d, J = 7.2 Hz, 1H), 1.92-1.70 (m, 6H), 1.55-1.15 (m, 18H), 1.13-1.09 (m, 6H), 0.71 (s, 3H); LC-ELSD / MS purity 99%, C 32 H 48 N3O4[M+H] + The MS ESI calculated value is 538, and the measured value is also 538. Example 10: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17S)-N-(5-fluoropyridine-2-yl)-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide (A47) [ka] A40 synthesis A solution of NaH (8.00 g, 200 mmol) in DMSO (100 mL) was added dropwise to a solution of trimethylsulfonium iodide (40.7 g, 200 mmol) in THF (100 mL) under N2 over 30 minutes at 0°C. The reaction mixture was then added to a solution of A39 (50 g, 182 mmol) in DMSO (100 mL). After stirring at room temperature for 12 hours, the residue was poured into ice water (w / w=1 / 1) (400 mL) and stirred for 20 minutes. The aqueous phase was extracted with ELISA (3 × 400 mL). The combined organic solution was washed with brine (2 × 200 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was ground from MeOH (300 mL) to obtain A40 (45 g) as a solid. 1 H NMR (400MHz, CDCl3) δ 2.67-2.37 (m, 2H), 2.28-2.13 (m, 2H), 2.12-2.04 (m, 1H), 1.99-1.89 (m, 1H), 1.88-1.72 (m, 4H), 1.70-1.60 (m, 2H), 1.58-1.43 (m, 5H), 1.41-1.04 (m, 8H), 0.92-0.82 (m, 3H). A41 synthesis Na (21.5 g, 935 mmol) was added to MeOH (250 mL) in fractions at room temperature. After stirring under N2 for 2 hours, MeOH (150 mL) containing A40 (45 g, 156 mmol) was added. After heating at 75 °C for 12 hours, the residue was poured into water (400 mL) and extracted with ethyl acetate (3 × 400 mL). The combined organic solution was washed with brine (2 × 200 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by flash column (0-15% ethyl acetate in PE) to obtain A41 (30 g) as an oil and A41a (12 g, 24.0%) as a solid. A41: 1 H NMR (400MHz, CDCl3) δ 3.47-3.31 (m, 5H), 2.42 (dd, J=8.4, 19.2 Hz, 1H), 2.12-2.02 (m, 1H), 1.96-1.89 (m, 1H), 1.86-1.67 (m, 6H), 1.60-1.41 (m, 7H), 1.38-1.17 (m, 7H), 1.10-1.00 (m, 1H), 0.85 (s, 3H). A42 synthesis Under N2 conditions, EtPPh3Br (30.0 g, 84.0 mmol) and t-BuOK (9.40 g, 84.0 mmol) were mixed in THF (100 mL) at 25°C. After stirring for 1 hour, a solution of A41 (9 g, 28.0 mmol) in THF (50 mL) was added. After stirring at 40°C for 3 hours, the solution was combined with two other batches prepared from 9 g and 18 g, respectively, and poured into NH4Cl aqueous solution (200 mL). The aqueous phase was extracted with SiO2 (3 × 200 mL). The combined organic solutions were washed with brine (2 × 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was ground with MeOH (300 mL) and water (300 mL) to obtain A42 (30 g) as an oil. 1 H NMR δ 5.17-5.05 (m, 1H), 3.46-3.32 (m, 5H), 2.59 (br s, 1H), 2.43-2.12 (m, 4H), 1.90-1.79 (m, 2H), 1.77-1.69 (m, 7H), 1.67-1.61 (m, 4H), 1.43-1.32 (m, 3H), 1.23-1.03 (m, 6H), 0.87 (s, 3H). A43 synthesis 9-BBN dimer (43.9g, 180mmol) was added to a solution of A42 (30g, 90.2mmol) in THF (150mL) at 25℃. After stirring for 1 hour, NaOH (108mL, 5M in water, 541mmol) was added at 0℃, followed by the dropwise addition of hydrogen peroxide (54.1mL, 541mmol). After stirring at 78℃ for 3 hours, the reaction product was quenched with saturated Na2S2O3 aqueous solution (100mL) and ice water (300mL). After stirring for 20 minutes, the aqueous phase was extracted with ELISA (3×250mL). The combined organic solution was washed with brine (2×250mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was ground with CH3OH (100 mL) and (500 mL) to obtain A43 (35 g) as oil, which was purified by flash column (0-15% ELISA in PE) to obtain A43 (12 g, 34%) as solid. 1 H NMR (400MHz, CDCl3) δ 3.74-3.66 (m, 1H), 3.43-3.36 (m, 5H), 2.60 (s, 1H), 1.95-1.71 (m, 6H), 1.64 (s, 4H), 1.60-1.44 (m, 6H), 1.35-1.19 (m, 6H), 1.16-1.08 (m, 4H), 0.92-0.80 (m, 1H), 0.75 (s, 1H), 0.65 (s, 3H). A44 synthesis To the solution of A43 in DCM (100 mL), DMP (33.1 g, 78.2 mmol) was added all at once at 25°C. After stirring at 35°C for 30 minutes, the residue was washed with NaHCO3 (100 mL), filtered, and then the mixture was washed with water (100 mL) containing Na2SO3 and NaHCO3 (3:1). The aqueous phase was extracted with DCM (100 mL). The organic solution was washed with brine (2 × 100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by flash column chromatography (PE with 0-15% ethyl acetate) to obtain A44 as a solid (5 g, 42%) and an impure product (4 g). The impure product was re-purified by silica gel chromatography (PE / ethyl acetate = 30 / 1 to 5 / 1) to obtain an additional A44 as a solid (2 g, 50%). 1 H NMR (400MHz, CDCl3) δ 3.45-3.34 (m, 5H), 2.62 (s, 1H), 2.59-2.46 (m, 1H), 2.26-2.13 (m, 1H), 2.13-2.09 (m, 1H), 2.11 (s, 3H), 2.03-1.97 (m, 1H), 2.03-1.97 (m, 1H), 1.83 (br d, J=15.2 Hz, 1H), 1.78-1.63 (m, 5H), 1.52-1.33 (m, 5H), 1.31-1.00 (m, 8H), 0.61 (s, 3H). 45 synthesis Br2 (2.73 g, 17.1 mmol) was added to an aqueous NaOH solution (2.74 g, 10% in water, 17.1 mmol) at 0°C. After stirring at 0°C for 30 minutes, the solution was added to a solution of A44 (2 g, 5.73 mmol) in dioxane (20 mL) and water (20 mL). After stirring at room temperature for 3 hours, the reaction mixture was washed with HCl (60 mL). The aqueous layer was acidified with HCl (12 M in water, 22 mL) to adjust the pH to 1 and stirred for 30 minutes. The precipitated solid was filtered off, washed with water (2 × 60 mL), and dried to obtain A45 (1.6 g, 59%) as a solid. 1H NMR (400MHz, CDCl3) δ 3.44-3.34 (m, 5H), 2.44-2.35 (m, 1H), 2.13-2.01 (m, 2H), 1.88-1.72 (m, 5H), 1.71-1.53 ​​(m, 5H), 1.51-1.31 (m, 7H), 1.30-1.18 (m, 4H), 1.09-0.99 (m, 2H), 0.72 (s, 3H). A46 synthesis To a solution of A45 (1.6 g, 4.56 mmol) in DMF (20 mL), HATU (2.59 g, 6.84 mmol) and DIPEA (2.35 g, 18.2 mmol) were added. After stirring at room temperature for 10 minutes, NH4Cl (487 mg, 9.12 mmol) was added. After stirring at room temperature for 16 hours, the residue was poured into water (50 mL) and extracted with SiO4 (3 × 40 mL). The combined organic solution was washed with brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain A46 (1.6 g) as a solid. The solid was dissolved in SiO4 (50 mL), washed with NH4Cl (2 × 50 mL) and LiCl (2 × 100 mL, 10 g in 200 mL of water), and concentrated under reduced pressure to obtain A46 (1.5 g, 94.3%) as a solid. 1 H NMR (400MHz, CDCl3) δ 5.43-5.18 (m, 2H), 3.46-3.34 (m, 5H), 2.63 (s, 1H), 2.23-2.07 (m, 2H), 2.23-2.07 (m, 1H), 1.96 (td, J=3.2, 12 Hz, 1H), 1.87-1.69 (m, 5H), 1.64-1.54 (m, 3H), 1.45-1.32 (m, 5H), 1.28-1.06 (m, 7H), 0.71 (s, 3H). A47 synthesis General method 10: A mixture of 2-chloro-5-fluoropyridine (75.2 mg, 0.5722 mmol), A46 (100 mg, 0.2861 mmol), xanthophos (16.5 mg, 0.02861 mmol), and cesium carbonate (187 mg, 0.5722 mmol) in dioxane (5 mL) was sprayed with nitrogen for 2 minutes, and then Pd2(dba)3 (26.1 mg, 0.02861 mmol) was added. After stirring at 110°C for 16 hours, the residue was poured into water (50 mL) and extracted with ethyl acetate (3 × 400 mL). The combined organic solution was washed with saturated brine (2 × 200 mL), dried over anhydrous sodium 2 SO4, and filtered. The solution was filtered and concentrated. The residue was purified by HPLC separation (column: YMC-Actus Triart C18 100×30mm×5um, gradient: 65-92%, conditions: water (0.05% HCl)-ACN, flow rate: 25 mL / min) to obtain A47 (24 mg, 19%) as a solid. 1 H NMR (400MHz, CDCl3) δ 8.30-8.19 (m, 1H), 8.10 (br s, 1H), 7.71 (br s, 1H), 7.47-7.38 (m, 1H), 3.40 (s, 5H), 2.63 (s, 1H), 2.71-2.59 (m, 1H), 2.42-2.20 (m, 2H), 2.03 (br d, J=16.5 Hz, 1H), 2.01-1.97 (m, 1H), 1.86-1.71 (m, 6H), 1.55-1.34 (m, 8H), 1.32-1.03 (m, 5H), 0.74 (s, 3H). 19 F NMR (376MHz, CDCl3) -132.876. LC-ELSD / MS purity 99%, C 26 H 38 FN2O3[M+H] + The MS ESI calculated value is 445, and the measured value is also 445. Example 11: Synthesis of (3R,5R,8S,9S,10S,13S,14S,17S)-N-(5-cyanopyrazine-2-yl)-3-(ethoxymethyl)-10-ethyl-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide (A49) [ka] A48 synthesis To a solution of A28 (200 mg, 0.509 mmol) in DMF (5 mL), HATU (183 mg, 0.763 mmol) and DIPEA (526 mg, 4.07 mmol) were added. After stirring at room temperature for 15 minutes, NH4Cl (108 mg, 2.03 mmol) was added. After stirring for 16 hours, the reaction mixture was diluted with  (50 mL), washed with water (10 mL), 3% LiCl aqueous solution (10 mL), water (10 mL), and brine (10 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash column (0-100%  in PE) to obtain A48 (180 mg, 90%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 5.27 (d, J=26.8 Hz, 2H), 3.58-3.50 (m, 2H), 3.46-3.35 (m, 2H), 2.74 (s, 1H), 2.20-2.10 (m, 2H), 1.98-1.90 (m, 2H), 1.80-1.56 (m, 7H), 1.56-1.15 (m, 17H), 0.80-0.74 (m, 3H), 0.70 (s, 3H); LC-ELSD / MS purity 99%, C 24 H 32 NO3[M +H] + The MS ESI calculated value is 392, and the measured value is also 392. A49 synthesis General method 11: A mixture of 5-chloropyrazine-2-carbonitride (85.3 mg, 0.612 mmol), A48 (160 mg, 0.408 mmol), xanthophos (23.6 mg, 0.041 mmol), and cesium carbonate (265 mg, 0.816 mmol) in dioxane (3 mL) was sprayed with nitrogen for 2 minutes, and then Pd2(dba)3 (37.3 mg, 0.041 mmol) was added. After heating in a microwave at 105°C for 1 hour, the reaction mixture was filtered, concentrated, and preparative HPLC (column Xtimate C18 150 × 25 mm × 5 μm; conditions water (0.225% FA)-ACN start B 90 The solution was purified using the following method: End B 100 gradient time (min) 7; 100% B retention time (min) 1, flow rate (ml / min) 25) to obtain A49 (38 mg, 19%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 9.60 (d, J=1.2 Hz, 1H), 8.54 (d, J=1.2 Hz, 1H), 7.83 (m, 1H), 3.57-3.50 (m, 2H), 3.46-3.35 (m, LC-ELSD / MS 99% purity, C 29 H 43 N4O3[M+H] + The MS ESI calculated value is 495, and the measured value is also 495. Example 12: Synthesis of (3R,5S,8S,9S,10S,13S,14S,17S)-N-(5-cyanopyridine-2-yl)-3-(ethoxymethyl)-10-ethyl-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide (A68) [ka] A51 synthesis To a solution of A50 (50.0 g, 165 mmol) in DCM (1000 mL), imidazole (16.7 g, 247 mmol) and TBSCl (37.2 g, 247 mmol) were added at room temperature. After 12 hours, the reaction product was purified together with another batch A51. The mixture was diluted with water (1000 mL) and extracted with DCM (3 × 600 mL). The combined organic solution was washed with 1 N HCl (500 mL), saturated NaHCO3 (500 mL), and saturated brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain A51 (110.0 g, 80%) as an oil. 1 1H NMR (400 MHz, CDCl3) δ H 5.87 (s, 1H), 4.00-3.80 (m, 2H), 2.68-2.25 (m, 6H), 2.15-1.45 (m, 9H), 1.30-1.00 (m, 4H), 0.91 (s, 3H), 0.85 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H). A52 synthesis Lithium (9.2g, 1314mmol) was divided and added to freshly prepared liquid ammonia (1.2L) at -70°C. After stirring at -70°C for 1 hour, A51 (110.0g, 263mmol) was added to dried THF (800mL) and t-butanol (38.9g, 5 A 26 mmol solution was added. After stirring at -70°C for 1 hour, ammonium chloride (500 g) was added, and the mixture was warmed to room temperature. After stirring for 16 hours, the reaction product was diluted with water (1 L) and extracted with dimethyl (3 × 500 mL). The combined organic solution was washed with aqueous HCl (1 M, 2 × 500 mL), saturated aqueous NaHCO3 (500 mL), and brine (1 L), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain A52 (110 g) as an oily substance, which was used directly in the next step without further purification. 1 1H NMR (400 MHz, CDCl3) δ H 3.95 (d, J = 10.8 Hz, 1H), 3.89 (d, J = 10.8 Hz, 1H), 3.70-3.62 (m, 1H), 2.55-2.42 (m, 2H), 2.35-2.25 (m, 1H), 2.18-2.05 (m, 1H), 1.90-1.52 (m, 9H), 1.50-1.17 (m, 7H), 1.10-0.84 (m, 15H), 0.10 (s, 3H), 0.08 (s, 3H). A53 synthesis To a solution of A52 (110 g, 261 mmol) in DCM (1500 mL), PCC (84.0 g, 391 mmol) and silica gel (100 g) were added. After stirring at room temperature for 1 hour, the suspension was filtered, and the filtrate cake was washed with DCM (2 × 500 mL). The combined filtrate was concentrated, and the material was purified by silica gel column chromatography (PE / ԅ = 10 / 1 to 5 / 1) to obtain A53 (56.0 g, 51.3%) as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 3.96 (d, J = 10.8 Hz, 1H), 3.89 (d, J = 10.8 Hz, 1H), 2.51-2.40 (m, 4H), 2.36-2.28 (m, 1H), 2.20-2.02 (m, 2H), 2.00-1.35 (m, 10H), 1.30-1.15 (m, 4H), 1.10-0.95 (m, 1H), 0.93-0.87 (m, 12H), 0.09 (s, 3H), 0.08 (s, 3H). A54 and A55 combination To a solution of A54 (24.0 g, 57.3 mmol) in toluene (250 mL), PPTS (2.86 g, 11.4 mmol) and ethane-1,2-diol (28.4 g, 458 mmol) were added. After stirring at 135 °C for 16 minutes in a Dean-Stark trap, the reaction mixture was concentrated, dissolved in Depositphotos (500 mL), washed with water (500 mL) and brine (300 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was ground from Depositphotos:PE (1:1, 50 mL) to obtain a solid mixture of A55 and A56, which was purified by silica gel chromatography (PE / Depositphotos = 4 / 1) to obtain A55 and A56 as solids. A55: 1 1H NMR (400 MHz, CDCl3) δ H 3.95-3.80 (m, 9H), 3.65 (d, J = 10.4 Hz, 1H), 2.27-2.20 (m, 1H), 2.03-1.87 (m, 1H), 1.83-1.32 (m, 14H), 1.30-1.15 (m, 3H), 1.05-0.75 (m, 15H), 0.05 (s, 3H), 0.04 (s, 3H). A56: 1 1H NMR (400 MHz, CDCl3) δ H 3.94 (s, 4H), 3.85 (d, J = 10.4 Hz, 1H), 3.65 (d, J = 10.0 Hz, 1H), 2.43 (dd, J = 6.6, 18.8 Hz, 1H), 2.27-2.17 (m, 1H), 2.00-1.87 (m, 2H), 1.82-1.35 (m, 11H), 1.28-1.12 (m, 5H), 1.07-0.95 (m, 2H), 0.92-0.88 (m, 12H), 0.06 (s, 3H), 0.05 (s, 3H). A57 synthesis To a solution of A55 (33.0 g, 65.1 mmol) in THF (300 mL), TBAF·3H2O (101.0 g, 325 mmol) was added. After stirring at 55°C for 12 hours, the mixture was poured into water (500 mL) and extracted with  (2 × 300 mL). The organic solution was washed with saturated brine (2 × 200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the product (25.5 g). This was purified by flash column (PE with 0-50% Â) to obtain A57 (18.7 g, 73.6%) as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 3.95-3.75 (m, 10H), 2.25-2.18 (m, 1H), 2.03-1.93 (m, 1H), 1.85-1.60 (m, 7H), 1.58-1.37 (m, 7H), 1.30-1.03 (m, 5H), 1.02-0.80 (m, 5H). A58 synthesis To a solution of A57 (18.7 g, 47.6 mmol) in DCM (200 mL), PCC (15.3 g, 71.4 mmol) and silica gel (20.0 g) were added at room temperature. After stirring for 1 hour, the suspension was filtered, and the filter cake was washed with DCM (2 × 100 mL). The combined filtrate was concentrated to obtain A58 (18.5 g) as a solid, which was used directly in the next step without further purification. 1 1H NMR (400 MHz, CDCl3) δ H 10.03 (s, 1H), 4.10-3.70 (m, 8H), 2.33 (d, J = 12.4 Hz, 1H), 2.10-1.15 (m, 18H), 1.13-1.00 (m, 3H), 0.76 (s, 3H). A59 synthesis To a suspension of MePPh3Br (50.3g, 141 mmol) in THF (200 mL), t-BuOK (15.8g, 141 mmol) was added. After stirring at 45°C for 0.5 hours, a solution of A58 (18.5g, 47.3 mmol) in THF (100 mL) was added. After stirring at 45°C for 1 hour, saturated NH4Cl solution (200 mL) was added to the mixture to separate the organic solution. The aqueous layer was collected and extracted with HCl (2 × 100 mL). The combined organic solution was washed with saturated brine (200 mL), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE / HCl = 10 / 1 to 4 / 1) to obtain A59 (13.6g, 74.3%) as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 5.88 (dd, J = 10.8, 17.6 Hz, 1H), 5.35 (dd, J = 11.2 Hz, 1H), 5.02 (dd, J = 1.2, 18.0 Hz, 1H), 4.00-3.82 (m, 8H), 2.20-2.12 (m, 1H), 2.00-1.90 (m, 1H), 1.85-1.12 (m, 18H), 1.07-0.92 (m, 1H), 0.90-0.80 (m, 1H), 0.74 (s, 3H). A60 synthesis To a solution of A59 (13.6 g, 35.0 mmol) in THF (80 mL), 12 M HCl (29.1 mL, 350 mmol) was added. After stirring at 15 °C for 16 hours, the reaction mixture was diluted with H₂O (50 mL) and adjusted to pH 9 with solid Na₂CO₃ (20 g). The aqueous layer was extracted with Depositphotos (3 × 200 mL). The combined organic solution was washed with saturated brine (200 mL), dried over anhydrous Na₂SO₄, filtered, concentrated (10.5 g), and purified by flash column (PE with 15-20% Depositphotos) to obtain A60 (8.0 g, 76.9%) as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 6.03 (dd, J = 11.2, 18.0 Hz, 1H), 5.52 (d, J = 11.2 Hz, 1H), 5.20 (d, J = 18.0 Hz, 1H), 2.55-2.40 (m, 3H), 2.32-1.55 (m, 13H), 1.55-1.15 (m, 4H), 1.10-0.95 (m, 1H), 0.93-0.8 3 (m, 1H), 0.80 (s, 3H). Synthesis of A61 To a solution of A60 (8.0 g, 26.6 mmol) in THF (200 mL), Pd-C (wet formula, 50%, 2.0 g) was added under Ar. The suspension was degassed under reduced pressure and purged with H2 three times. After hydrogenation with 30 psi hydrogen at room temperature for 16 hours, the reaction mixture was filtered through a Celite pad and washed with THF (2 × 200 mL). The filtrate was concentrated under reduced pressure and purified by flash column (PE with 15-20% Â) to obtain A61 (8.0 g, 99.5%) as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 2.55-2.25 (m, LC-ELSD / MS purity 99%, C 20 H 31 O2[M+H] + The MS ESI calculated value is 303, and the measured value is also 303. A62 synthesis To a stirred solution of Me3SiO (4.35 g, 19.8 mmol) in DMSO (30 mL) and THF (30 mL), NaH (791 mg, 19.8 mmol, 60% in oil) was added in fractions at 0°C. After stirring under N2 for 1 hour, the mixture was added to a solution of A61 (5.0 g, 16.5 mmol) in DMSO (30 mL). After stirring at room temperature for 16 hours, the reaction mixture was poured into ice water (300 mL) and extracted with dimethylethanol (2 × 100 mL). The combined organic solution was washed with water (2 × 100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain A62 (5.0 g) as an oily substance, which was used as is. 1 1H NMR (400 MHz, CDCl3) δ H 2.61 (s, 2H), 2.42 (dd, J = 8.8, 19.6 Hz, 1H), 2.15-1.40 (m, 11H), 1.35-1.05 (m, 8H), 1.02-0.70 (m, 10H). A63 synthesis To a freshly prepared solution of sodium ethoxy (31.5 mL, 31.5 mmol, 1 M in EtOH), anhydrous ethanol (20 mL) containing A62 (1.0 g, 3.15 mmol) was added. After stirring at 75°C for 16 hours, the reaction product was diluted with water (50 mL) and concentrated to remove most of the solvent. The mixture was extracted with ethyl acetate (2 × 30 mL). The combined organic solution was washed with saturated brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography (0-40% ethyl acetate in PE) to obtain A63 (512 mg, 44.9%) as an oily substance. 1 1H NMR (400 MHz, CDCl3) δ H 3.52 (q, J = 6.8 Hz, 2H), 3.21 (s, 2H), 2.42 (dd, J = 8.8, 19.6 Hz, 1H), 2.15-1.50 (m, 9H), 1.50-1.10 (m, 15H), 1.05-0.99 (m, 1H), 0.95 (t, J = 7.6 Hz, 3H), 0.90-0.65 (m, 4H); LC-ELSD / MS 99% purity, C 23 H 38 O3Na [M+Na] + The MS ESI calculated value is 385, and the measured value is also 385. A64 synthesis To a suspension of bromo(ethyl)triphenylphosphoran (22.4 g, 60.4 mmol) in THF (100 mL), t-BuOK (6.76 g, 60.4 mmol) was added under N2 conditions at 15 °C. After stirring at 45 °C for 1 hour, a solution of A63 (5.5 g, 15.1 mmol) in THF (100 mL) was added. After stirring at 45 °C for 16 hours, the mixture was treated with NH4Cl (300 mL). The organic solution was separated, and the recovered aqueous phase was extracted with ELISA (2 × 150 mL). The combined organic solution was washed with brine (2 × 100 mL). The mixture was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column (0-15% toluene in PE) to obtain A64 (5.0 g, 88%) as an oily substance. 1 1H NMR (400 MHz, CDCl3) δ H 5.15-5.05 (m, 1H), 3.52 (q, J = 6.8 Hz, 2H), 3.21 (s, 2H), 2.40-2.10 (m, 4H), 1.85-1.75(m, 1H), 1.70-1.40 (m, 7H), 1.35-1.10 (m, 14H), 1.10-0.80 (m, 11H). A65 synthesis A 9-BBN dimer (3.90 g, 16.0 mmol) was added to a solution of A64 (3.0 g, 8.0 mmol) in THF (50 mL). After stirring at room temperature for 16 hours, the mixture was cooled to 0°C, and ethanol (3.68 g, 80.0 mmol), followed by NaOH (16 mL, 5 M, 80.0 mmol), was slowly added. After the addition was complete, H2O2 (8.01 mL, 80.0 mmol, 30%) was slowly added, maintaining the internal temperature below 15°C. After stirring at 75°C for 1 hour, the reaction mixture was work-up and purified together with another batch (performed on the same scale). Saturated Na2S2O3 aqueous solution (300 mL) was added, and the mixture was stirred for a further 1 hour at 0°C. The mixture was diluted with water (200 mL) and extracted with ELISA (3 × 100 mL). The combined organic solution was washed with saturated brine (200 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain A65 (5.0 g) as an oily substance, which was used as is. 1 1H NMR (400 MHz, CDCl3) δ H 3.75-3.65 (m, 1H), 3.51 (q, J = 6.8 Hz, 2H), 3.20 (s, 2H), 1.95-1.75 (m, 12H), 1.74-1.40 (m, 13H), 1.39-0.95 (m, 8H), 0.92 (t, J = 7.6 Hz, 3H), 0.66 (s, 3H). A66 synthesis To a solution of A65 (0.8 g, 2.0 mmol) in DCM (20 mL), PCC (872 mg, 4.1 mmol) and silica gel (1 g) were added. After stirring at room temperature for 3 hours, the reaction mixture was filtered, and the residue was washed with anhydrous DCM (2 × 50 mL). The combined organic solution was concentrated under reduced pressure and purified by flash column (PE with 0-20% ethyl phosphate) to obtain A66 (0.75 g, 94.6%) as a solid. 1 1H NMR (400 MHz, CDCl3) δ H3.52 (q, J = 6.8 Hz, 2H), 3.21 (s, 2H), 2.52 (t, J = 8.8 Hz, 1H), 2.25-2.10 (m, 5H), 2.05-1.95 (m, 1H), 1.90-1.80 (m, 1H), 1.75-1.65 (m, 4H), 1.55-1.05 (m, 18H), 1.00-0.80 (m, 5H), 0.62 (s, 3H); LC-ELSD / MS purity 99%, C 25 H 41 O2[M-H2O+H] + The MS ESI calculated value is 373, and the measured value is also 373. A67 synthesis Liquid bromine (1.22 g, 7.7 mmol) was slowly added at 0°C to a vigorously stirred aqueous sodium hydroxide solution (10.2 mL, 3 M, 30.7 mmol). When all the bromine had dissolved, the mixture was slowly added to a stirred solution of A66 (1.0 g, 2.6 mmol) in dioxane (18 mL) and water (6 mL). After stirring at room temperature for 16 hours, the reaction mixture was quenched with an aqueous Na2SO3 solution (30 mL) and hydrochloric acid was added. A precipitate formed when the pH was adjusted with acid (3N). The suspension was diluted with ethyl acetate (50 mL), and the organic phase was recovered. The aqueous phase was extracted with ethyl acetate (2 × 50 mL). The combined organic solution was washed with saturated brine (50 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure to obtain A67 (0.8 g, 80%) as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 3.71 (s, 1H), 3.52 (q, J = 6.8 Hz, 2H), 3.21 (s, 2H), 2.37 (t, J = 9.2 Hz, 1H), 2.15-2.00 (m, 3H), 1.90-1.70 (m, 2H), 1.60-1.10 (m, 20H), 1.00-0.65 (m, 5H), 0.74 (s, 3H). A68 synthesis To a solution of A67 (200 mg, 0.5 mmol) in pyridine (5 mL), EDCI (389 mg, 2.0 mmol) was added. After stirring at room temperature for 10 minutes, 6-aminopyridine-3-carbonitride (120 mg, 1.0 mmol) was added. After stirring at 45 °C for 16 hours, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic solution was washed with saturated brine (2 × 20 mL), dried over anhydrous sodium 2 SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column (10-20% ethyl acetate in PE) to obtain A68 (26 mg, 10.3%) as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 8.52 (d, J = 1.6 Hz, 1H), 8.36 (d, J = 8.8 Hz, 1H), 7.92 (dd, J = 2.4, 6.4 Hz, 1H), 7.86 (s, 1H), 3.52 (q, J = 6.8 Hz, 2H), 3.21 (s, LC-ELSD / MS 99% purity, C 30 H 44 N3O3[M+H] + The MS ESI calculated value is 494, and the measured value is also 494. Example 13: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethyl-N-(2-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide (A69) [ka] To a solution of A14 (50 mg, 0.111 mmol) in EtOH (5 mL), Pd / C (50 mg, over 50% water) was added. After hydrogenation at 25°C for 16 hours under 30 psi of hydrogen, the mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to obtain the product. This was purified by SFC (column: DAIEL CHIRALCEL OD-H (250 mm × 30 mm, 5 μm)), gradient: 40-40% B (A = 0.1% NH3 / H2O, B = MeOH), flow rate: 60 mL / min) to obtain ST-320-018-024 (Rt: 4.870, 39 mg, 65%) as a solid. 1 H NMR (400 MHz, MeOD) δ 3.67 (t, J=5.8 Hz, 2H), 2.74 (t, J=6.4 Hz, 2H), 2.47 (t, J=9.2 Hz, 1H), 2.25-2.11 (m, 1H), 2.02 (s, 3H), 2.00-1.93 (m, 3H), 1.92-1.83 (m, 5H), 1.82-1.65 (m, 4H), 1.56-1.28 (m, 11H), 1.24 (s, 3H), 1.21-1.08 (m, 4H), 0.77 (s, 3H); LC-ELSD / MS purity 98%, C 28 H 44 N3O2[M+H] + The MS ESI calculated value is 454, and the measured value is also 454. Example 14: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17S)-N-(5-cyanopyrazine-2-yl)-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide (A75) [ka] A71 synthesis To a solution of 19-norpregnane-20-one,3-hydroxy-,(3α,5β)-(CAS No. 16051-97-1) (500 mg, 1.64 mmol), imidazole (334 mg, 4.92 mmol), and DMAP (386 mg, 1.64 mmol) in DCM (10 mL), TBSCl (988 mg, 6.56 mmol) was added under N2 conditions at 0°C. After stirring at 30°C for 16 hours, the mixture was diluted with water (15 mL) and extracted with DCM (35 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain a solid (610 mg). This was purified by flash column (PE with 0-5% Â) to obtain A71 (590 mg, 86%) as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 3.64-3.52 (m, 1H), 2.53 (t, J=8.9 Hz, 1H), 2.23-2.07 (m, 4H), 2.02-1.81 (m, 2H), 1.78-1.59 (m, 6H), 1.52-1.38 (m, 4H), 1.34-0.96 (m, 10H), 0.92-0.87 (m, 9H), 0.60 (s, 3H), 0.09-0.03 (m, 6H). A72 synthesis Br2 (1.18 g, 7.44 mmol) was added to an aqueous NaOH solution (10% in water, 11.7 g, 29.7 mmol) at 0°C. After stirring at 0°C for 30 minutes, the resulting mixture was added to a solution of A71 (590 mg, 1.40 mmol) in dioxane (6 mL). After stirring at 25°C for 6 hours, HBrO and Br2 (1.18 g, 7.44 mmol) from another batch prepared from an aqueous NaOH solution (10% in water, 11.7 g, 29.7 mmol) were added to the reaction mixture at 0°C. After further stirring at room temperature for 16 hours, the reaction mixture was diluted with an aqueous Na2SO3 solution (15 mL) and stirred at 75°C for 1 hour. After cooling to room temperature, the pH was adjusted to 3-4 with HCl (4 M) and stirred for 30 minutes. The precipitated solid was filtered and dried to obtain A72 (514 mg, 87%) as a rubbery substance. 11H NMR (400 MHz, CDCl3) δ H 3.58 (m, 2H), 2.34 (m, 1H), 2.08-2.01 (m, 2H), 1.94-1.60 (m, 8H), 1.59-1.36 (m, 2H), 1.33-0.98 (m, 11H), 0.89 (s, 9H), 0.70 (s, 3H), 0.12--0.04 (m, 6H). A73 synthesis To a solution of A72 (300 mg, 0.713 mmol) in DMF (8 mL), HATU (809 mg, 2.13 mmol) and DIPEA (275 mg, 2.13 mmol) were added. After stirring at 25°C for 30 minutes, NH4Cl (190 mg, 3.56 mmol) was added. The following was added. After stirring at 25°C for 16 hours, the reaction mixture was diluted with water (50 mL) and extracted with toluene (50 mL). The organic solution was washed with brine (3 × 50 mL), dried over sodium sulfate, filtered, and concentrated. The residue was ground with PE (10 mL) to obtain A73 (160 mg) as an oil, which was purified by flash column (PE with 0-60% toluene) to obtain A73 (60 mg, 38%) as an oil. 1 1H NMR (400 MHz, CDCl3) δ H 5.51-5.15 (m, 2H), 3.69-3.48 (m, 1H), 2.24-2.06 (m, 2H), 2.00-1.83 (m, 3H), 1.70-1.61 (m, 6H), 1.53-1.37 (m, 4H), 1.35-1.03 (m, 9H), 0.89 (s, 9H), 0.76-0.68 (m, 3H), 0.06 (s, 6H). A74 synthesis To a solution of A73 (60 mg, 0.142 mmol) in THF (2 mL), TBAF (295 mg, 1.13 mmol) was added. After stirring at 60°C for 16 hours, the mixture was poured into water (15 mL) and extracted with ₹ (2 × 30 mL). The combined organic solution was washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the product. This product was purified by preparative HPLC (column Xtimate C18 150 × 25 mm × 5 μm, conditions water (0.225% FA)-ACN, start B: 28%, end B: 58%, gradient time (min) 7.5, 100% B, retention time (min) 2; flow rate (ml / min) 30) to obtain A74 (9.2 mg, 21%) as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 5.46-5.11 (m, 2H), 3.64 (m, 1H), 2.26-2.06 (m, 2H), 2.01-1.86 (m, 2H), 1.85-1.56 (m, 9H), 1.50-1.34 (m, 3H), 1.32-1.04 (m, 9H), 0.72 (s, 3H); LC-ELSD / MS purity 99%, C 19 H 32 NO2 [M+H] + The MS ESI calculated value is 306, and the measured value is also 306. A75 synthesis A mixture of A74 (200 mg, 0.654 mmol), 5-bromopyrazine-2-carbonitride (239 mg, 1.30 mmol), xanthophos (37.8 mg, 0.065 mmol), and Cs2CO3 (423 mg, 1.30 mmol) in dioxane (10 mL) was sprayed with nitrogen for 2 minutes, and then Pd2(dba)3 (59.8 mg, 0.065 mmol) was added. After stirring at 115°C for 16 hours, the reaction mixture was filtered through a Celite pad and extracted with DCM (3 × 20 mL). The combined organic solution was concentrated and purified by flash column (0-25% ethyl acetate in PE) to obtain A75 (35 mg, 13%) as a solid. 1 1H NMR (400MHz, CDCl3) δ H9.67 (d, J=1.3 Hz, 1H), 8.55 (d, J=1.5 Hz, 1H), 7.84 (s, 1H), 3.70-3.60 (m, 1H), 2.49-2.38 (m, 1H), 2.31-2.23 (m, 1H), 2.01-1.95 (m, 1H), 1.88-1.60 (m, 9H), 1.56-1.05 (m, 13H), 0.75 (s, 3H). LC-ELSD / MS purity 99%, C 24 H 33 N4O2[M+H] + The MS ESI calculated value is 409, and the measured value is also 409. Example 15: Synthesis of (3R,5R,8R,9S,10S,13S,14S,17S)-N-(3-chloro-6-methylpyridine-2-yl)-3-ethyl-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide (A80) [ka] A77 synthesis AlMe3 (25.5 mL, 51.0 mmol, 2 M in toluene) was added dropwise to a solution of 2,6-di-tert-butyl-4-methylphenol (22.5 g, 102 mmol) in toluene (50 mL) at 0°C. The mixture was stirred at 25°C for 1 hour and used directly as the MAD solution. To the MAD (51.0 mmol), a solution of pregnane-3,20-dione,(5β)-(5 g, 15.7 mmol) in DCM (25 mL) was added dropwise at -70°C. After stirring under N2 at -70°C for 1 hour, bromo(ethyl)magnesium (15.6 mL, 47.0 mmol, 3 M in ethyl ether) was added dropwise at -70°C. After stirring at -70°C for a further 1 hour, the reaction mixture was poured into saturated citric acid aqueous solution (50 mL) at below 10°C, then ice water (60 mL) was added and the mixture was stirred for a further 10 minutes. The aqueous phase was extracted with dimethyl phosphate (2 × 40 mL). The combined organic solution was washed with brine (20 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated. The residue was purified by flash column (10% dimethyl phosphate in PE) to obtain A77 (3.7 g) as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 2.59-2.46 (m, 1H), 2.22-2.09 (m, 4H), 2.04 (s, 1H), 2.03-1.97 (m, 1H), 1.94-1.78 (m, 2H), 1.73-1.63 (m, 3H), 1.62-1.35 (m, 8H), 1.31-1.20 (m, 6H), 1.19-0.95 (m, 3H), 0.93 (s, 3H), 0.88 (t, J = 7.6 Hz, 3H), 0.59 (s, 3H). A78 synthesis Br2 (2.52 g, 15.8 mmol) was added to an aqueous NaOH solution (1.90 g, 10% in water, 47.5 mmol). The mixture was stirred at 0°C for 30 minutes and then added to a solution of A77 (1.1 g, 3.17 mmol) in dioxane (6 mL) and water (2 mL). After stirring at 25°C for 2 hours, the reaction mixture was washed with SiO2 (20 mL), and the aqueous layer was acidified with HCl (12 M in water, 12 mL) to adjust the pH to 1, and stirred for 30 minutes. The precipitated solid was filtered, washed with water (2 × 12 mL), dried, and purified by flash column (0-30% SiO2 in PE) to obtain A78 (1.06 g) as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 2.39 (t, J = 9.6 Hz, 1H), 2.15-2.01 (m, 2H), 1.94-1.80 (m, 3H), 1.70 (br d, J = 14.4 Hz, 3H), 1.59 (td, J = 7.6, 14.9 Hz, 5H), 1.45 (br dd, J = 10.4, 19.6 Hz, 7H), 1.31-1.18 (m, 6H), 0.94 (s, 3H), 0.88 (t, J = 7.6 Hz, 3H), 0.71 (s, 3H). LC-ELSD / MS purity 99%, C 22 H 35 O2[M-H2O+H] + MS ESI calculated value: 331, measured value: 331 A79 synthesis To a solution of A78 (530 mg, 1.52 mmol) at room temperature in DMF (5 mL), HATU (866 mg, 2.28 mmol) and DIPEA (785 mg, 6.08 mmol), followed by NH4Cl (161 mg, 3.04 mmol), were added. After stirring for 16 hours, the reaction mixture was poured into water (50 mL) and extracted with SiO (3 × 40 mL). The combined organic phase was washed with brine (2 × 50 mL), then washed with LiCl (3 × 50 mL, 5% in water), dried over anhydrous Na2SO4, filtered, and concentrated to obtain A79 (266 mg) as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 5.25 (br d, J = 11.6 Hz, 2H), 2.23-2.08 (m, 2H), 2.02-1.95 (m, 1H), 1.93-1.61 (m, 6H), 1.54-1.35 (m, 8H), 1.34-1.06 (m, 9H), 0.94 (s, 3H), 0.88 (t, J = 7.6 Hz, 3H), 0.70 (s, 3H). LC-ELSD / MS purity 99%, C 22 H 38 NO2 [M+H] + MS ESI calculated value: 348, measured value: 348 A80 synthesis A mixture of 2,3-dichloro-6-methylpyridine (79.8 mg, 0.493 mmol), A79 (150 mg, 0.449 mmol), xanthophos (25.9 mg, 0.0449 mmol), and Cs2CO3 (172 mg, 0.898 mmol) in dioxane (3 mL) was sprayed with nitrogen for 2 minutes, and then Pd2(dba)3 (41.1 mg, 0.0449 mmol) was added. After stirring at 130°C for 16 hours, the mixture was poured into water (8 mL) and extracted with siRNA (2 × 8 mL). The combined organic solution was washed with brine (8 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column (0-75% siRNA in PE) to obtain A80 (120.2 mg, 57%) as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 7.58 (d, J = 8.0 Hz, 1H), 7.48 (s, 1H), 6.92 (d, J = 8.4 Hz, 1H), 2.52 (s, 3H), 2.50-2.44 (m, 1H), 2.37-2.28 (m, 1H), 2.14 (br d, J = 10.3 Hz, 1H), 1.94-1.79 (m, 3H), 1.77-1.61 (m, 3H), 1.56-1.36 (m, 8H), 1.35-1.15 (m, 8H), 1.05-0.97 (m, 1H), 0.94 (s, 3H), 0.88 (t, J = 7.6 Hz, 3H), 0.79 (s, 3H); LC-ELSD / MS purity 99%, C 28 H 42 ClN2O2[M+H] + The MS ESI calculated value is 473, and the measured value is also 473. Example 16: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17S)-N-(3-chloro-6-methylpyridine-2-yl)-3-ethyl-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide (A85) [ka] A82 synthesis To a solution of BHT (12 g, 54.4 mmol) in toluene (120 mL) at 0°C under nitrogen, trimethylaluminum (2 M in toluene, 14 mL, 28 mmol) was added dropwise. The mixture was stirred at 25°C for 1 hour and used directly as a MAD solution without further purification. To the above newly prepared MAD solution, a solution of A81 (6 g, 19.8 mmol, CAS number 10594-58-8) in DCM (60 mL) was added dropwise at -70°C. After stirring at -70°C under N2 for 1 hour, EtMgBr (20 mL, 60 mmol, 3 M in ethyl ether) was added dropwise at -70°C. After stirring at -70°C for 1 hour, the reaction mixture was poured into saturated citric acid aqueous solution (600 mL) at less than 10°C and extracted with DCM (2 × 800 mL). The combined organic solution was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the product, which was then ground with PE (10 mL) to obtain A82 (3.83 g, 58%) as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 2.56-2.50 (m, 1H), 2.24-2.10 (m, 4H), 2.07-1.99 (m, 1H), 1.89-1.51 (m, 9H), 1.50-1.20 (m, 12H), 1.19-1.00 (m, 3H), 0.98-0.80 (m, 3H), 0.61 (s, 3H). A83 synthesis Br2 (2.39 g, 15 mmol) was added to an aqueous NaOH solution (10% in water, 1.9 g, 47.5 mmol). The mixture was stirred at 0°C for 30 minutes and added to a solution of A82 (1 g, 3 mmol) in dioxane (9 mL) and water (3 mL). After stirring at 25°C for 2 hours, the reaction mixture was washed with HCl (10 mL). The aqueous layer was acidified to approximately pH 1 with HCl (12 M in water, 12 mL) and stirred for 30 minutes. The precipitated solid was filtered off, washed with water (2 × 12 mL), dried, and purified by flash column (0-30% HCl in PE) to obtain A83 (500 mg, 50%) as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 2.43-2.38 (m, 1H), 2.20-2.00 (m, 2H), 1.87-1.57 (m, 8H), 1.56-149 (m, 3H), 1.48-1.25 (m, 10H), 1.24-1.00 (m, 4H), 0.89-0.72 (m, 3H), 0.73 (s, 3H). A84 synthesis To a solution of A83 (500 mg, 1.49 mmol) in DMF (3 mL), HATU (847 mg, 2.23 mmol) and DIPEA (770 mg, 5.96 mmol) were added. After stirring at room temperature for 10 minutes, ammonia chloride (157 mg, 2.98 mmol) was added. After stirring overnight, the reaction mixture was poured into water (8 mL) and extracted with ₹ (3 × 8 mL). The combined organic solution was washed with brine (2 × 8 mL). The organic phase was washed with LiCl (3 × 8 mL, 5% in water), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain A84 (300 mg, 60%) as a solid. 11H NMR (400 MHz, CDCl3) δ H 6.00-5.85 (m, 1H), 5.70-5.55 (m, 1H), 2.26-2.24 (m, 1H), 2.23-2.10 (m, 1H), 2.0-1.85 (m, 1H), 1.80-154 (m, 9H), 1.50-1.20 (m, 12H), 1.20-1.05 (m, 3H), 0.95-0.82 (m, 3H), 0.90 (s, 3H). A85 synthesis A mixture of 2,3-dichloro-6-methylpyridine (73 mg, 0.45 mmol), A84 (150 mg, 0.449 mmol), xanthophos (26 mg, 0.044 mmol), and Cs2CO3 (300 mg, 0.923 mmol) in dioxane (3 mL) was sprayed with nitrogen for 2 minutes, and then Pd2(dba)3 (42 mg, 0.045 mmol) was added. After stirring at 130°C for 16 hours, the reaction mixture was poured into water (8 mL) and EtO2 was added. Extraction was performed with Ac (2 × 8 mL). The combined organic solution was washed with brine (8 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by flash column (0-75%  in PE) to obtain A85 (76.6 mg) as a solid, which was combined with another batch of 63.6 mg prepared from 150 mg of A84. The combined material (140 mg) was purified by SFC (column: DAIEL CHIRALPAK AS-H (250 mm × 30 mm, 5 μm), conditions: 0.1% NH₃H₂O EtOH, start B: 30%, end B: 30%, flow rate (ml / min): 65) to obtain A85 (101 mg) as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 7.58 (d, J=8.0, 1H), 7.26 (s, 1H), 6.91 (d, J=8.0, 1H), 2.52-2.48 (m, 4H), 2.30-2.25 (m, 1H), 2.20-2.10 (m, 1H), 1.90-1.70 (m, 6H), 1.69-1.51 (m, 6H), 1.50-1.25 (m, 12H), 0.90-0.86 (m, 3H), 0.81 (m, 3H). LC-ELSD / MS 99% purity, C 27 H 40 The MS ESI calculated value for ClN2O2[M+H]+ is 459, and the measured value is also 459. The following examples were prepared using the listed reaction products and SM, following the general procedures in Examples 1 to 16. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] [Table 3-12] [Table 3-13] [Table 3-14] [Table 3-15] [Table 3-16] [Table 3-17] [Table 3-18] [Table 3-19] [Table 3-20] [Table 3-21] [Table 3-22] [Table 3-23] Example 66: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17S)-3-(ethoxymethyl)-N-(2-fluoropyridine-3-yl)-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide (A89) [ka] A87 synthesis Liquid bromine (6.55 g, 41.0 mmol) was slowly added at 0°C to a vigorously stirred aqueous sodium hydroxide solution (54.6 mL, 3 M, 164 mmol). When all the bromine had dissolved, the mixture was diluted with cold dioxane (15 mL) and slowly added to a stirred solution of A86 (5 g, 13.7 mmol) in dioxane (20 mL) and water (15 mL). A homogeneous yellow solution slowly became colorless, and a white precipitate formed. After stirring at 25°C for 5 hours, the remaining oxidizing agent was quenched with an aqueous Na2S2O3 solution (30 mL), and then the mixture was heated to 80°C until the solid material dissolved. The solution was acidified with HCl (3 M, 40 mL), and a white solid precipitated. The solid was filtered and washed with water (3 × 100 mL) to obtain a solid, which was dried under reduced pressure to obtain A87 (5 g) as a solid. 1 H NMR (400 MHz, CDCl3) δ 11.89 (br s, 1H), 4.13 (br s, 1H), 3.46 (q, J=7.0 Hz, 2H), 3.32-3.26 (m, 2H), 2.29 (t, J = 9.2 Hz, 1H), 1.99-1.89 (m, 2H), 1.78-1.46 (m, 7H), 1.41-1.14 (m, 11H), 1.11 (t, J = 7.0 Hz, 3H), 1.07-0.91 (m, 3H), 0.62 (s, 3H). A88 synthesis A solution of A87 (150 mg, 0.411 mmol) in DMF (3 mL) contains HATU (234 mg, 0.616 mmol) and DIPEA (211 mg, 1.64 mmol) were added. After stirring at 25°C for 15 minutes, NH4Cl (43.9 mg, 0.822 mmol) was added. After stirring at 25°C for 16 hours, the mixture was poured into water (15 mL) and extracted with RINKAN (2 × 30 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was analyzed by HPLC (column: Xtimate C18 150 × 25 mm, 5 μm; conditions: water (0.04% NH3H2O ​​+ 10 mM)). A88 (64 mg, 42.9%) was purified by NH4HCO3-ACN (gradient: holding B from 34% to 59% for 9 minutes and at 100% for 2 minutes; flow rate: 30 mL / min) to obtain A88 as a solid. 1 H NMR (400 MHz, CDCl3) δ 5.25 (d, J = 15.6 Hz, 2H), 3.53 (q, J = 7.2 Hz, 2H), 3.43 (q, J = 9.2 Hz, 2H), 2.73 (s, 1H), 2.23-2.08 (m, 2H), 1.99-1.92 (m, 1H), 1.86-1.58 (m, 8H), 1.50-1.34 (m, 6H), 1.21 (s, 10H), 0.72 (s, 3H). LCMS: 100% purity, C 22 H 38 NO3 [M+H] + The MS ESI calculated value is 364, and the measured value is also 364. A89 synthesis A mixture of A88 (300 mg, 0.825 mmol), Pd2(dba)3 (75.5 mg, 0.0825 mmol), xanthophos (47.7 mg, 0.0825 mmol), Cs2CO3 (537 mg, 1.65 mmol), and 3-bromo-2-fluoropyridine (290 mg, 1.65 mmol) in dioxane (4 mL) was stirred at 100°C for 16 hours under N2 conditions. The reaction mixture was combined with another batch derived from 100 mg of A88. The combined reaction was quenched with water (10 mL) and extracted with  (3 × 10 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column (10% to 50%  in PE) to obtain A89 (260 mg) as a solid. A89 (60 mg, 0.130 mmol) was further purified by preparative HPLC (column: Phenomenex Gemini-NX 150 × 30 mm × 5 μm; conditions: water (0.04% NH3H2O ​​+ 10 mM NH4HCO3)-ACN; start B: 58%, end B: 88%; gradient time (min): 8; 100% B retention time (min): 2; flow rate (ml / min): 30) to obtain A89 (16.8 mg, 28.1%) as a solid. 11H NMR (400 MHz, CDCl3) δ H 8.81-8.72 (m, 1H), 7.89-7.83 (m, 1H), 7.22-7.14 (m, 2H), 3.58-3.49 (m, 2H), 3.48-3.38 (m, 2H), 2.74 (s, 1H), 2.41-2.33 (m, 1H), 2.32-2.20 (m, 1H), 2.06-1.98 (m, 1H), 1.91-1.70 (m, 6H), 1.68-1.58 (m, 2H), 1.54-1.36 (m, 7H), 1.34-1.06 (m, 9H), 0.73 (s, 3H). 19 F NMR (376.5 MHz, CDCl3) δ F -83.93. LC-ELSD / MS purity >99%, C 27 H 40 FN2O3[M +H] + The MS ESI calculated value is 459, and the measured value is also 459. Example (EXASMLE) 67: Synthesis of (3R, 5R, 8R, 9R, 10S, 13S, 14S, 17S)-N-(5-cyanopyridine-2-yl)-3-hydroxy-13-methyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide (A94) [ka] A91 synthesis To a solution of 2,6-di-tert-butyl-4-methylphenol (13.1 g, 59.6 mmol) in toluene (20 mL), AlMe3 (14.9 mL, 29.8 mmol, 2 M in toluene) was added dropwise at 0°C. After stirring at 25°C for 30 minutes, a solution of A90 (3 g, 9.91 mmol) in anhydrous toluene (40 mL) was added dropwise to the MAD solution at -70°C. After stirring at -70°C for 1 hour under N2, n-PrMgCl (14.8 mL, 29.7 mmol, 2 M in diethyl ether) was added dropwise at -70°C. After stirring at -70°C for 2 hours, the reaction mixture was poured into saturated citric acid aqueous solution (100 mL) at 10°C and extracted with ELISA (2 × 100 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column (0-10% siRNA in PE) to obtain A91 (1.7g, 49%) as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 2.53 (t, J = 8 Hz, 1H), 2.16-2.11 (m, 4H), 2.04-1.98 (m, 1H), 1.83-1.52 (m, 3H), 1.50-1.30 (m, 5H), 1.27-1.02 (m, 10H), 0.97-0.77 (m, 11H), 0.61 (s, 3H). A92 synthesis Liquid bromine (1.92 g, 12.0 mmol) was slowly added at 0°C to a vigorously stirred aqueous sodium hydroxide solution (15.0 mL, 4 M, 60.2 mmol). When all the bromine had dissolved, the mixture was slowly added to a stirred solution of A91 (700 mg, 2.0 mmol) in dioxane (12 mL) and water (3 mL). A homogeneous yellow solution slowly became colorless, and a white precipitate formed. After stirring at 25°C for 16 hours, the remaining oxidizing agent was quenched with an aqueous Na2SO3 solution (30 mL, saturated), and then the mixture was heated at 80°C until the solid material dissolved. Acidification of the solution with hydrochloride acid (3 M, 40 mL) yielded a white precipitate. The solid was filtered and washed with water (3 × 50 mL) to obtain a solid, which was dried under reduced pressure to obtain A92 (600 mg, 86%) as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 2.41 (t, J = 9.2 Hz, 1H), 2.18-1.98 (m, 2H), 1.95-1.59 (m, 9H), 1.52-1.28 (m, 9H), 1.25-1.00 (m, 9H), 0.93 (t, J = 7.6 Hz, 3H), 0.73 (s, 3H). A93 synthesis To a solution of A92 (600 mg, 1.72 mmol) in DMF (10 mL), HATU (977 mg, 2.57 mmol), Et3N (868 mg, 8.60 mmol), and NH4Cl (184 mg, 3.44 mmol) were added. After stirring at 40°C for 16 hours, the mixture was added to water (100 mL) and filtered. The filtered cake was washed with water (2 × 50 mL) and concentrated to obtain A93 (600 mg) as a solid. A93 (400 mg, 1.15 mmol) was ground in acetonitrile (5 mL) at 20°C to obtain A93 (155.7 mg, 39%) as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 5.35-5.15 (m, 2H), 2.25-2.05 (m, 2H), 2.02-1.90 (m, 1H), 1.90-1.60 (m, 7H), 1.52-1.30 (m, 9H), 1.28-1.05 (m, 10H), 0.93 (t, J = 7.6 Hz, 3H), 0.72 (s, 3H).LC-ELSD / MS purity 99%, C 22 H 38 NO2[M +H] + The MS ESI calculated value is 348.3, and the measured value is 348.3. A94 synthesis Pd2(dba)3 (52.6 mg, 0.058 mmol) was added in a single dose under N2 to a solution of A93 (200 mg, 0.58 mmol), 6-chloropyridine-3-carbonitrile (159 mg, 1.15 mmol), X-Phos (27.3 mg, 0.058 mmol), and Cs2CO3 (374 mg, 1.15 mmol) in dioxane (10 mL). After stirring at 101 °C for 20 hours, the residue was poured into water (50 mL) and extracted with  (3 × 20 mL). The combined organic phase was washed with brine (2 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column (0-30%  in PE) to obtain A94 (140 mg) as a solid. A94 (140 mg, 0.311 mmol) was ground with acetonitrile (2 mL) at 20°C to obtain A94 (71.3 mg, 51%) as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 8.53 (d, J = 1.6 Hz, 1H), 8.37 (d, J = 8.8 Hz, 1H),7.92 (dd, J=2.0, 8.8 Hz, 1H), 7.86 (s, 1H), 2.37 (t, J = 8.8 Hz, 1H), 2.35-2.20 (m, 1H), 2.03-1.95 (m, 1H), 1.95-1.59 (m, 8H), 1.52-1.30 (m, 13H), 1.28-1.05 (m, 5H), 0.94 (t, J = 7.2 Hz, 3H), 0.73 (s, 3H).LC-ELSD / MS purity 99%, C 28 H40 N3O2[M +H] + The MS ESI calculated value is 450.3, and the measured value is 450.3. Example 68: Synthesis of (3R, 5R, 8R, 9S, 10S, 13S, 14S, 17S)-N-(5-cyanopyridine-2-yl)-3-hydroxy-10,13-dimethyl-3-propylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide (A99) [ka] A96 synthesis To a solution of 2,6-di-t-butyl-p-cresol (butylated hydroxytoluene) (33.5 g, 152 mmol) in toluene (100 mL) at 0°C under nitrogen, trimethylaluminum (2 M in toluene, 38 mL, 76 mmol) was added dropwise. After stirring at 20°C for 1 hour, a solution of A95 (8.0 g, 25.2 mmol) in toluene (50 mL) was added dropwise to the above solution at -70°C under N2. After stirring at -70°C for 1 hour, n-PrMgCl (37.8 mL, 75.6 mmol, 2 M in THF) was added dropwise. After stirring at -70°C for 0.5 hours, the reaction mixture was poured into ice-cold citric acid aqueous solution (500 mL) and extracted with dimethyl (2 × 500 mL). The combined organic layer was washed with brine (2 × 300 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated. The residue was combined with another solution of the crude product and purified by flash column (0-25%  in PE) to obtain A96 (5.9 g) as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 2.53 (t, J = 8.8 Hz, 1H), 2.19-2.13 (m, 1H), 2.11 (s, 3H), 2.06-1.64 (m, 6H), 1.54-1.36 (m, 11H), 1.32-1.00 (m, 9H), 0.96-0.91 (m, 6H), 0.59 (s, 3H). A97 synthesis Liquid bromine (1.32 g, 8.28 mmol) was slowly added at 0°C to a vigorously stirred aqueous sodium hydroxide solution (10.3 mL, 4 M, 41.4 mmol). When all the bromine had dissolved, the mixture was slowly added to a stirred solution of A96 (500 mg, 1.38 mmol) in dioxane (10 mL) and water (2.5 mL). A homogeneous yellow solution slowly became colorless, and a white precipitate formed. After stirring at 25°C for 16 hours, the reaction mixture was acidified with HCl (4 M in water, 13 mL) to adjust the pH to 1, and stirred for 30 minutes. The precipitated solid was filtered off, washed with water (2 × 30 mL), and dried to obtain A97 (500 mg) as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 2.42-2.04 (m, 3H), 1.88-1.46 (m, 13H), 1.39-1.01 (m, 13H), 0.96-0.91 (m, 6H), 0.71 (s, 3H) A98 synthesis To a solution of A97 (500 mg, 1.37 mmol) in DMF (10 mL), HATU (779 mg, 2.05 mmol), Et3N (693 mg, 6.85 mmol), and NH4Cl (146 mg, 2.74 mmol) were added. After stirring at 40°C for 16 hours, the mixture was added to water (100 mL) and stirred at 15°C for 10 minutes. The mixture was filtered; the filtered cake was washed with water (2 × 30 ml) to obtain A98 (1.2 g) as a solid, which was then used as... A98 (250 mg) was obtained as a solid by grinding acetonitrile (20 ml) at 15°C. 1 1H NMR (400 MHz, CDCl3) δ H 5.34-5.16 (m, LC-ELSD / MS: Purity 99%;C 23 H 40 NO2[M +H]+ The MS ESI calculated value is 362.3, and the measured value is 362.3. A99 synthesis To a solution of A98 (150 mg, 0.41 mmol), 6-chloropyridine-3-carbonitride (114 mg, 0.83 mmol), X-Phos (19.7 mg, 0.041 mmol), and Cs2CO3 (270 mg, 0.83 mmol) in dioxane (10 mL), Pd2(dba)3 (37.9 mg, 0.041 mmol) was added in one step under N2 conditions. After stirring at 110 °C for 16 hours, the residue was poured into water (50 mL) and extracted with ELISA (3 × 40 mL). The combined organic phase was washed with brine (2 × 50 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column (0-40%  in PE) to obtain A99 (100 mg), which was then ground in acetonitrile (5 ml) at 15°C to obtain A99 (31.0 mg, 31%) as a solid. 1 1H NMR (400 MHz, CDCl3) δ H 8.53 (d, J=1.2 Hz, 1H), 8.37 (d, J=8.8 Hz, 1H), 7.92 (dd, J=2.2, 8.8 Hz, 1H), 7.85 (s, 1H), 2.39-2.21 (m, 2H), 2.04-1.67 (m, 6H), 1.54-1.36 (m, 10H), 1.36-0.98 (m, 10H), 0.97-0.91 (m, 6H), 0.71 (s, 3H).LC-ELSD / MS: 99% purity, C 29 H 42 N3O2[M +H] + The MS ESI calculated value is 464.3, and the measured value is 464.3. TBPS-binding steroid inhibition A [35S]-t-butylbicyclophosphorothionate (TBPS) binding assay using rat cortical membrane in the presence of 5 mM GABA has been reported (Gee et al., J. Pharmacol. Exp. Ther. 1987, 241, 346-353; Hawkinson et al., Mol. Pharmacol. 1994, 46, 977-985; Lewin, AH et al., Mol. Pharmacol. 1989, 35, 189-194).

[0325] In short, after decapitation of carbon dioxide-anesthetized Sprague-Dawley rats (200-250g), the cortex is promptly removed. The cortex is homogenized in 10 volumes of ice-cold 0.32M sucrose using a glass / Teflon® homogenizer and centrifuged at 4°C and 1500×g for 10 minutes. The supernatant is centrifuged at 4°C and 10,000×g for 20 minutes to obtain a P2 pellet. The P2 pellet is resuspended in 200mM NaCl / 50mM sodium potassium phosphate pH 7.4 buffer and centrifuged at 4°C and 10,000×g for 10 minutes. This washing procedure is repeated twice, and the pellet is resuspended in 10 volumes of buffer. Aliquots (100mL) of the membrane suspension are used to extract 3nM [ 35 Incubate 5 mL aliquots of the test drug (final 0.5%) dissolved in dimethyl sulfoxide (DMSO) in the presence of [S]-TBPS and 5 mM GABA. This incubation yields a final volume of 1.0 mL including buffer. Nonspecific binding is measured in the presence of 2 mM unlabeled TBPS, ranging from 15 to 25%. After incubation at room temperature for 90 minutes, terminate the assay by filtration through a glass fiber filter (Schleicher and Schuell No. 32) using a cell harvester (Brandel), and rinse three times with ice-cold buffer. The radioactivity bound to the filter is measured by liquid scintillation spectrometry. Nonlinear curve fitting of the overall data for each drug, averaged for each concentration, is performed using Prism (GraphPad). If the sum of squares is significantly lower by the F-test, the data is fitted to a partial inhibition model instead of a complete inhibition model. Similarly, if the sum of squares is significantly lower by the F-test, the data is fitted to a two-component inhibition model instead of a one-component inhibition model. The concentration of the test compound that yields 50% inhibition of specific binding (IC) 50 ) and the maximum degree of inhibition (I max The mean ± SEM of each individual experiment is then calculated using the same model that was used for the entire dataset. Picrotoxin serves as a positive control for these studies because it has been demonstrated to strongly inhibit TBPS binding.

[0326] Various compounds in vitro 35 Screening may be performed or may be performed to measure the potential of [S]-TBPS binding as a regulator. These assays may be performed or may be performed according to the above.

[0327] In Table 2 below, A represents TBPS ICs with a minimum of 0.1 μM. 50 (μM) is shown, and B is TBPS IC from 0.1 μM to less than 1 μM. 50 (μM) is shown, and C is 1.0 μM or greater in TBPS ICs. 50 (μM) is shown. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12] [Table 2-13] [Table 2-14]

[0328] Equivalents and range In a claim, an article (e.g., “a,” “an,” and “the”) may mean one or more unless otherwise indicated or evident from the context. Unless otherwise indicated or evident from the context, a claim or description containing “or” between one or more members of a group is considered to satisfy that one, more than one, or all group members are present in, used in, or otherwise related to a given product or process. The present invention includes embodiments in which exactly one member of the group is present in, used in, or otherwise related to a given product or process. The present invention includes embodiments in which more than one or all group members are present in, used in, or otherwise related to a given product or process.

[0329] Furthermore, the present invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims are introduced in another claim. For example, any claim dependent on another claim may be modified to include one or more limitations found in any other claim dependent on the same basic claim. Where elements are presented as a list, for example in the form of a Markush group, each subgroup of that element is also disclosed, and any element may be removed from that group. In general, where the present invention or an aspect of the present invention is referred to as including certain elements and / or features, it should be understood that certain embodiments of the present invention or an aspect of the present invention consist of or essentially consist of such elements and / or features. For the sake of simplicity, those embodiments are not explicitly shown herein in these terms. Note that the terms “comprising” and “containing” are intended to be open and may also include further elements or steps. Where a scope is given, the endpoint is included. Furthermore, unless otherwise indicated or evident from the context and the understanding of those skilled in the art, values ​​expressed as ranges may, unless the context clearly indicates otherwise, assume any specific value or subrange within the ranges described in the various embodiments of the present invention up to one-tenth of the lower limit unit of that range.

[0330] This application refers to various issued patents, published patent applications, academic articles, and other publications (all of which are incorporated herein by reference). In the event of any conflict between any reference incorporated herein and this specification, this specification shall prevail. Furthermore, any particular embodiment of the Invention that falls within the scope of the Prior Art may be expressly excluded from any one or more of the claims. Such embodiments are considered to be known to those skilled in the art and may be excluded even if such exclusion is not expressly indicated herein. Any particular embodiment of the Invention, whether or not it relates to the existence of the Prior Art, may be expressed in any way. A claim may be excluded for any reason.

[0331] Those skilled in the art will be able to recognize or verify, by mere conventional experimental methods, many equivalents to the specific embodiments described herein. The scope of the embodiments described herein is not intended to be limited to the above description, as is set forth in the appended claims. Those skilled in the art will recognize that various changes and modifications to this description can be made without departing from the spirit or scope of the invention as defined in the following claims.

Claims

1. A composition for treating a disease in a subject requiring treatment of a disease, wherein the composition is in an effective amount of formula (I) for use in a method for treating a disability in a subject requiring treatment of a disability: 【Chemistry 96】 The compound comprises the following, wherein the disorder is a neuroendocrine disorder, a neurodegenerative disorder, an anxiety disorder, a women's health disorder, epilepsy, or a seizure; In equation (I), 【Chemistry 97】 When the bond valency is permissible, it represents a single or double bond; R ２ａ 、R ２ｂ 、R ４ａ 、R ４ｂ 、R ６ 、R ７ 、R １１ａ 、and R １１ｂ each independently is hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, -OR Ｄ１ 、-OC(=O)R Ｄ１ 、-NH ２ 、-N(R Ｄ１ ) ２ 、or -NR Ｄ１ C(=O)R Ｄ１ where R in each case Ｄ１ is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when bonded to an oxygen atom, a nitrogen protecting group when bonded to a nitrogen atom, or two R Ｄ１ groups are bonded to form a substituted or unsubstituted heterocyclic ring; or one of R ２ａ and R ２ｂ 、R ４ａ and R ４ｂ 、R ７ａ and R ７ｂ 、R １１ａ and R １１ｂ is bonded to form an oxo(=O) group; R １６ and R １７ Each of these is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR Ａ１ , -SR Ａ１ , -N(R Ａ１ ) ２ , -N(R Ａ１ ), -CN(R Ａ１ ) ２ , -C(O)R Ａ１ -OC(=O)R Ａ１ , -OC(=O)OR Ａ１ , -OC(=O)SR Ａ１ , -OC(=O)N(R Ａ１ ) ２ , -SC(=O)R Ａ２ , -SC(=O)OR Ａ１ , -SC(=O)SR Ａ１ , -SC(=O)N(R Ａ１ ) ２ , -NHC(=O)R Ａ１ , -NHC(=O)OR Ａ１ , -NHC(=O)SR Ａ１ , -NHC(=O)N(R Ａ１ ) ２ , -OS (=O) ２ R Ａ２ , -OS (=O) ２ OR Ａ１ , -S-S (=O) ２ R Ａ２ , -S-S (=O) ２ OR Ａ１ , -S(=O)R Ａ２ , -SO ２ R Ａ２ , or -S (=O) ２ OR Ａ１ And here, R in each case Ａ１ These are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group when bonded to an oxygen atom, sulfur protecting group when bonded to a sulfur atom, nitrogen protecting group when bonded to a nitrogen atom, -SO ２ R Ａ２ , -C(O)R Ａ２ is either or two R Ａ１ The groups bond to form substituted or unsubstituted heterocyclic rings or heteroaryl rings; R Ａ２ is 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; R ３ is hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; 【Chem.98】 If it is a single bond, R ５ is hydrogen or methyl; 【Chem.99】 If R is a double bond, ５ It does not exist; R １９ is hydrogen or a substituted or unsubstituted alkyl group; R Ｘ These are independently hydrogen, or a substituted or unsubstituted alkyl, and R Ｙ teeth, (a) 【Chemistry 100】 Selected from, Here, R in each case Ｄ is independently halogen, -NO ２ , -CN, -OR ＧＡ , -N(R ＧＡ ), -C(=O)R ２ , -C(=O)OR ＧＡ , -C(=O)N(R ＧＡ ), -OC(=O)R ＧＡ , -OC(=O)OR ２ , -N(R ＧＡ ), -OC(=O)N(R ＧＡ ), -N(R ＧＡ ), -C(=O)OR ＧＡ , -S(=O) ＧＡ R ２ , -S(=O) ＧＡ OR ＧＡ , -OS(=O) ２ R ＧＡ , -S(=O) ２ N(R ＧＡ ), or -N(R ２ ), -S(=O) ＧＡ R ２ , or is a substituted or unsubstituted C ＧＡ alkyl, substituted or unsubstituted C ２ alkenyl, substituted or unsubstituted C ＧＡ alkynyl, substituted or unsubstituted C ２ carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, C ＧＡ substituted or unsubstituted aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, or, if necessary, two R １～６ together with intervening atoms form a substituted or unsubstituted 3- to 4-membered carbocyclic ring or heterocyclic ring;​​​​​​​​​​ Here, R in each case ＧＡ These are independently hydrogen, substituted or unsubstituted C １～６ Alkyl, substituted, or unsubstituted C ２～６ Alkenyl, substituted or unsubstituted C ２～６ Alkynyl, substituted or unsubstituted C ３～６ Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group when bonded to oxygen, nitrogen protecting group when bonded to nitrogen, or two R ＧＡ The group combines with an intervening atom to form a substituted or unsubstituted carbocyclic ring or a heterocyclic ring; Here, R in each case Ｘ１ is hydrogen, or a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted carbocyclyl. R Ｙ but 【Chemistry 101】 If so, e is 0, 1, 2, 3, 4, or 5, and R Ｙ but 【Chemical Engineering 102】 If so, e is 1, 2, 3, 4, or 5; (b) 【Chemistry 103】 Selected from, Here, R in each case Ｄ These are independently halogen, substituted, or unsubstituted C １～６ Alkyl, -CN, substituted or unsubstituted 5- to 6-membered heteroaryl, substituted or unsubstituted 5-membered heterocyclyl, R Ｙ but 【Chemical 104】 If so, e is 0, 1, 2, 3, or 4; and R Ｙ but 【Chemistry 105】 If so, e is 1, 2, 3, or 4; (c) 【Chemistry 106】 【Chemistry 107】 Selected from, Here, R is -CH ３ ien-CH ２ CH ３ , -i-Pr, cyclopropyl or -CN; (d) 【Chemistry 108】 Selected from; (e) 【Chemistry 109】 is; or (f) 【Chemical 110】 That is, composition.

2. A composition for treating a disease in a subject requiring treatment of a disease, wherein the composition is in an effective amount of formula (I) for use in a method for treating a disability in a subject requiring treatment of a disability: 【Chemistry 111】 The compound comprises a pharmaceutically acceptable salt thereof, wherein the disorder is a neuroendocrine disorder, a neurodegenerative disorder, an anxiety disorder, a women's health disorder, epilepsy, or a seizure; In equation (I), 【Chemistry 112】 When the bond valency is permissible, it represents a single or double bond; R ２ａ , R ２ｂ , R ４ａ , R ４ｂ , R ６ , R ７ , R １１ａ , and R １１ｂ Each of these independently consists of hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, -OR Ｄ１ -OC(=O)R Ｄ１ , -NH ２ , -N(R Ｄ１ ) ２ , or -NR Ｄ１ C(=O)R Ｄ１ And here, R in each case Ｄ１ Independently, R is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, an oxygen protecting group when bonded to an oxygen atom, a nitrogen protecting group when bonded to a nitrogen atom, or two R groups. Ｄ１ The groups bond to form substituted or unsubstituted heterocyclic rings; or R ２ａ and R ２ｂ , R ４ａ and R ４ｂ , R ７ａ and R ７ｂ , R １１ａ and R １１ｂ One of them combines to form an oxo (=O) group; R １６ and R １７ Each of these is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR Ａ１ , -SR Ａ１ , -N(R Ａ１ ) ２ , -N(R Ａ１ ), -CN(R Ａ１ ) ２ , -C(O)R Ａ１ -OC(=O)R Ａ１ , -OC(=O)OR Ａ１ , -OC(=O)SR Ａ１ , -OC(=O)N(R Ａ１ ) ２ , -SC(=O)R Ａ２ , -SC(=O)OR Ａ１ , -SC(=O)SR Ａ１ , -SC(=O)N(R Ａ１ ) ２ , -NHC(=O)R Ａ１ , -NHC(=O)OR Ａ１ , -NHC(=O)SR Ａ１ , -NHC(=O)N(R Ａ１ ) ２ , -OS (=O) ２ R Ａ２ , -OS (=O) ２ OR Ａ１ , -S-S (=O) ２ R Ａ２ , -S-S (=O) ２ OR Ａ１ , -S(=O)R Ａ２ , -SO ２ R Ａ２ , or -S (=O) ２ OR Ａ１ And here, R in each case Ａ１ These are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group when bonded to an oxygen atom, sulfur protecting group when bonded to a sulfur atom, nitrogen protecting group when bonded to a nitrogen atom, -SO ２ R Ａ２ , -C(O)R Ａ２ is either or two R Ａ１ The groups bond to form substituted or unsubstituted heterocyclic rings or heteroaryl rings; R Ａ２ is 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; R ３ is hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; 【Chemistry 113】 If it is a single bond, R ５ is hydrogen or methyl; 【Chemistry 114】 If R is a double bond, ５ It does not exist; R １９ is hydrogen or a substituted or unsubstituted alkyl group; R Ｘ These are independently hydrogen, or a substituted or unsubstituted alkyl, and R Ｙ teeth, (a) 【Chemical 115】 Selected from, Here, R in each case Ｄ These are independently halogen, -NO ２ -CN, -OR ＧＡ , -N(R ＧＡ ) ２ , -C(=O)R ＧＡ , -C (=O) OR ＧＡ , -C(=O)N(R ＧＡ ) ２ -OC(=O)R ＧＡ , -OC(=O)OR ＧＡ , -N(R ＧＡ )C(=O)R ＧＡ , -OC(=O)N(R ＧＡ ) ２ , -N(R ＧＡ )C (=O)OR ＧＡ , -S (=O) ２ R ＧＡ , -S (=O) ２ OR ＧＡ , -OS (=O) ２ R ＧＡ , -S (=O) ２ N(R) ＧＡ ) ２ , or -N(R ＧＡ )S (=O) ２ R ＧＡ , substitution or non-substitution C １～６ Alkyl, substituted, or unsubstituted C ２～６ Alkenyl, substituted or unsubstituted C ２～６ Alkynyl, substituted or unsubstituted C ３～４ Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, C ５～１０ A substituted or unsubstituted aryl, a substituted or unsubstituted 5- to 10-membered heteroaryl, or two R as appropriate. ＧＡ These atoms combine with intervening atoms to form substituted or unsubstituted 3-4 membered carbocyclic or heterocyclic rings; Here, R in each case ＧＡ These are independently hydrogen, substituted or unsubstituted C １～６ Alkyl, substituted, or unsubstituted C ２～６ Alkenyl, substituted or unsubstituted C ２～６ Alkynyl, substituted or unsubstituted C ３～６ Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group when bonded to oxygen, nitrogen protecting group when bonded to nitrogen, or two R ＧＡ The group combines with an intervening atom to form a substituted or unsubstituted carbocyclic ring or a heterocyclic ring; Here, R in each case Ｘ１ is hydrogen, or a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted carbocyclyl. R Ｙ but 【Chemistry 116】 If so, e is 0, 1, 2, 3, 4, or 5, and R Ｙ but 【Chemistry 117】 If so, e is 1, 2, 3, 4, or 5; (b) 【Chemistry 118】 Selected from, Here, R in each case Ｄ These are independently halogen, substituted, or unsubstituted C １～６ Alkyl, -CN, substituted or unsubstituted 5- to 6-membered heteroaryl, substituted or unsubstituted 5-membered heterocyclyl, R Ｙ but 【Chemical 119】 If so, e is 0, 1, 2, 3, or 4; and R Ｙ but 【Chemical 120】 If so, e is 1, 2, 3, or 4; (c) 【Chemistry 121】 【Chemistry 122】 Selected from, Here, R is -CH ３ ien-CH ２ CH ３ , -i-Pr, cyclopropyl or -CN; (d) 【Chemical 123】 Selected from; (e) 【Chemistry 124】 is; or (f) 【Chemistry 125】 That is, composition.

3. R １９ The composition according to claim 1 or 2, wherein is hydrogen or methyl.

4. R ２ａ and R ２ｂ teeth, (a) Each independently of hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR Ｄ１ -OC(=O)R Ｄ１ , -NH ２ , or -N(R Ｄ１ ) ２ And here, R in each case Ｄ１ These are independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. (b) Each independently of hydrogen, substituted or unsubstituted C １ ~C ６ Alkyl, substituted, or unsubstituted C １ ~C ６ Haloalkyl, substituted, or unsubstituted C １ ~C ６ alkoxy, substituted or unsubstituted C １ ~C ６ Is it an alkoxyhalo or an -OH group? (c) Each independently contains hydrogen, -CH ３ ien-CH ２ CH ３ -OH, -OCH ３ , or -CH(CH ３ ) ２ is it, or (d) Each is independently hydrogen, The composition according to any one of claims 1 to 3.

5. R ４ａ and R ４ｂ teeth, (a) Each independently of hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR Ｄ１ -OC(=O)R Ｄ１ , -NH ２ , or -N(R Ｄ１ ) ２ And here, R in each case Ｄ１ These are independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. (b) Independently, hydrogen, substituted or unsubstituted C １ ~C ６ Alkyl, substituted, or unsubstituted C １ ~C ６ Haloalkyl, substituted, or unsubstituted C １ ~C ６ alkoxy, substituted or unsubstituted C １ ~C ６ Is it an alkoxyhalo or an -OH group? (c) Independently, hydrogen, -CH ３ ien-CH ２ CH ３ -OH, -OCH ３ , or -CH(CH ３ ) ２ is it, or (d) Each is independently hydrogen, The composition according to any one of claims 1 to 4.

6. R １１ａ and R １１ｂ teeth, (a) Each independently of hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR Ｄ１ -OC(=O)R Ｄ１ , -NH ２ , or -N(R Ｄ１ ) ２ And here, R in each case Ｄ１ These are independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. (b) Independently, hydrogen, substituted or unsubstituted C １ ~C ６ Alkyl, substituted, or unsubstituted C １ ~C ６ Haloalkyl, substituted, or unsubstituted C １ ~C ６ Alkoxy, or substituted or unsubstituted C １ ~C ６ Is it an alkoxyhalo? (c) Independently, hydrogen, -CH ３ ien-CH ２ CH ３ -OH, -OCH ３ , or -CH(CH ３ ) ２ is it, or (d) Each is independently hydrogen, The composition according to any one of claims 1 to 5.

7. R ７ teeth, (a) independently, hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR Ｄ１ -OC(=O)R Ｄ１ , -NH ２ , or -N(R Ｄ１ ) ２ And here, R in each case Ｄ１ These are independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. (b) Independently, hydrogen, substituted or unsubstituted C １ ~C ６ Alkyl, substituted, or unsubstituted C １ ~C ６ Haloalkyl, substituted, or unsubstituted C １ ~C ６ alkoxy, substituted or unsubstituted C １ ~C ６ Is it an alkoxyhalo or an -OH group? (c) Independently, hydrogen, -CH ３ ien-CH ２ CH ３ -OH, -OCH ３ , or -CH(CH ３ ) ２ is it, or (d) Hydrogen, The composition according to any one of claims 1 to 6.

8. R ６ teeth, (a) independently, hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR Ｄ１ -OC(=O)R Ｄ１ , -NH ２ , or -N(R Ｄ１ ) ２ And here, R in each case Ｄ１ These are independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. (b) Independently, hydrogen, substituted or unsubstituted C １ ~C ６ Alkyl, substituted, or unsubstituted C １ ~C ６ Haloalkyl, substituted, or unsubstituted C １ ~C ６ alkoxy, substituted or unsubstituted C １ ~C ６ Is it an alkoxyhalo or an -OH group? (c) Independently, hydrogen, -CH ３ ien-CH ２ CH ３ -OH, -OCH ３ , or -CH(CH ３ ) ２ is it, or (d) Hydrogen, The composition according to any one of claims 1 to 7.

9. R １６ teeth, (a) independently, hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR Ｄ１ -OC(=O)R Ｄ１ , -NH ２ , or -N(R Ｄ１ ) ２ And here, R in each case Ｄ１ These are independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. (b) Independently, hydrogen, substituted or unsubstituted C １ ~C ６ Alkyl, substituted, or unsubstituted C １ ~C ６ Haloalkyl, substituted, or unsubstituted C １ ~C ６ alkoxy, substituted or unsubstituted C １ ~C ６ Is it an alkoxyhalo or an -OH group? (c) Independently, hydrogen, -CH ３ ien-CH ２ CH ３ -OH, -OCH ３ , or -CH(CH ３ ) ２ is it, or (d) Hydrogen, The composition according to any one of claims 1 to 8.

10. R １７ teeth, (a) independently, hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR Ｄ１ -OC(=O)R Ｄ１ , -NH ２ , or -N(R Ｄ１ ) ２ And here, R in each case Ｄ１ These are independently hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. (b) Independently, hydrogen, substituted or unsubstituted C １ ~C ６ Alkyl, substituted, or unsubstituted C １ ~C ６ Haloalkyl, substituted, or unsubstituted C １ ~C ６ alkoxy, substituted or unsubstituted C １ ~C ６ Is it an alkoxyhalo or an -OH group? (c) Independently, hydrogen, -CH ３ ien-CH ２ CH ３ -OH, -OCH ３ , or -CH(CH ３ ) ２ is it, or (d) Hydrogen, The composition according to any one of claims 1 to 9.

11. R １９ teeth, (a) Independently, hydrogen, or substituted or unsubstituted C １ ~C ６ Alkyl, (b) Independently, hydrogen, or substituted or unsubstituted C １ ~C ４ Alkyl, (c) Independently, hydrogen, -CH ３ ien-CH ２ CH ３ , or -CH ２ OCH(CH ３ ) ２ , (d) Hydrogen, or (e)-CH ２ OCH(CH) ３ ) ２ The composition according to any one of claims 1 to 10.

12. R ３ teeth, (a) Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl (b) Substituted or unsubstituted alkyl, (c) Substitute or non-substitute C １ ~C ６ Alkyl The composition according to any one of claims 1 to 11.

13. The compound of formula (I) is of formula (I-a): 【Chemistry 126】 It is a compound of, Here, R １ is either a substituted or unsubstituted alkyl group, or The compound of formula (I) is formula (I-b1) or formula (I-b2): 【Chemistry 127】 It is a compound of, or The compound of formula (I) is formula (I-c1) or formula (I-c2): 【Chemistry 128】 It is a compound of, or The compound of formula (I) is of formula (I-d1) or formula (I-d2). 【Chemistry 129】 It is a compound of, or The compound of formula (I) is of formula (I-e): 【Chemistry 130】 It is a compound of the form R １ ha-CH ２ CH ３ or -CH ３ is, or The compound of formula (I) is of formula (I-f): 【Chemistry 131】 It is a compound of, or The compound of formula (I) is of formula (I-g) 【Chemistry 132】 It is a compound of The composition according to any one of claims 1 to 12.

14. R １ teeth, (a)-CH ２ CH ３ or -CH ３ Is it 、 (b)-CH ２ CH ３ is it, or (c)-CH ３ That is, The composition according to claim 13.

15. R Ｘ teeth, (a) Independently, hydrogen, or substituted or unsubstituted C １～６ Alkyl, (b) Independently, hydrogen, or substituted or unsubstituted C １～４ Alkyl, (c) Independently, hydrogen, -CH ３ , or -CH ２ CH ３ ,or (d) Hydrogen The composition according to any one of claims 1 to 14.

16. R Ｙ teeth, (a) 【Chemistry 133】 Selected from; Here, R is -CH ３ ien-CH ２ CH ３ , -i-Pr, cyclopropyl, or -CN, (b) 【Chemistry 134】 Select from, (c) 【Chemistry 135】 is it, or (d) 【Transformation 136】 That is, The composition according to any one of claims 1 to 15. 【Request Item 17】 【Chemistry 137-1】 【Chemistry 137-2】 【Chemistry 137-3】 【Chemistry 137-4】 【Chemistry 137-5】 【Chemistry 137-6】 【Chemistry 137-7】 【Chemistry 137-8】 【Chemistry 137-9】 【Chemistry 137-10】 【Chemistry 137-11】 【Chemistry 137-12】 【Chemistry 137-13】 【Chemistry 137-14】 【Chemistry 137-15】 【Chemistry 137-16】 【Chemistry 137-17】 A composition according to any one of claims 1 to 16, selected from the group consisting of the following.

18. The composition according to claim 1, wherein the disorder is an anxiety disorder.

19. The composition according to claim 18, wherein the anxiety disorder is generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, phobia, or post-traumatic stress disorder.

20. The composition according to claim 1, wherein the disorder is epilepsy.

21. The composition according to claim 1, wherein the disorder is a seizure. 【Request Item 22】 【Chemistry 139】 A compound selected from the group consisting of the following.

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