C7, C12, and C16 replacement neurostimulant steroids and their methods of use

Abstract

To provide novel and improved neuroactive steroids that act as modulating agents for brain excitability, as well as agents for the prevention and treatment of CNS-related diseases, and methods for use thereof.SOLUTION: Described herein are C7, C12, and C16 substituted neuroactive steroids, having the following structures, and / or pharmaceutically acceptable salts thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] References of related applications This application claims priority to U.S. applications No. 62 / 360,887 (filed July 11, 2016), No. 62 / 360,884 (filed July 11, 2016), and No. 62 / 360,876 (filed July 11, 2016). These U.S. applications are incorporated herein by reference. [Background technology]

[0002] background 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 mediators 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 the GABA receptor complex (GRC), its effect on brain excitability is mediated by the neurotransmitter 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 the GRC, GABA facilitates 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 the effects of GABA (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 at least one distinct site for interaction with 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 occur endogenously. The most potent endogenous neurostimulant steroids are 3α-hydroxy-5-reduced pregnane-20-one and 3□□-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); Harrison, NL et al., J Pharmacol. Exp. Ther. 241:346-353 (1987).

[0006] Novel and improved neurostimulant steroids are needed that act as modulators of brain excitability and as agents for the prevention and treatment of CNS-related disorders. The compounds, compositions, and methods described herein are intended for this purpose. [Prior art documents] [Non-patent literature]

[0007] [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 Initiative] [Means for solving the problem]

[0008] The compounds of the present invention described herein, in certain embodiments, are, for example, GABA A They act as GABA regulators, either positively or negatively affecting the receptor. Such compounds act as GABA regulators. A It is expected to possess CNS activity, acting as a regulator of central nervous system (CNS) excitability mediated by its ability to modulate receptors.

[0009] Therefore, in another aspect, there is provided a method of treating a CNS-related disorder in a subject that requires treatment of the CNS-related disorder, the method comprising administering to the subject an effective amount of a compound described herein (e.g., a compound of formula (I), a compound of formula (V), or a compound of formula (IX)). In certain embodiments, the CNS-related disorder is selected from the group consisting of sleep disorder, mood disorder, schizophrenia spectrum disorder, spasm 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, and tinnitus. In certain embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered chronically. In certain embodiments, the compound is administered continuously, for example, by continuous intravenous infusion.

[0010] In one aspect, provided herein is Formula (I):

Chemical formula

Chemical formula

[0011] In some embodiments, R 3 It is an alkyl group.

[0012] In some embodiments, the compound of formula (I) is formula (Ia) or (Ib): [ka] It is a compound of [the compound].

[0013] In some embodiments, R 2 , R 4 , and R 6 , R 11a , and R 11b Each of them is independently a hydrogen atom.

[0014] In some embodiments, R 2 , R 4 , R 6 , R 11a , and R 11b These are all hydrogen. In some embodiments, R 2 , R 4 , and R 6Each of them is independently a halogen, a C1-C6 alkyl, a C1-C6 alkoxy, or -OH; in some embodiments, R 3 This is a C1-C6 alkyl group (for example, a C1-C6 haloalkyl group or -CH3 group).

[0015] In some embodiments, the compound of formula (I) is formula (II-a) or (II-b): [ka] It is a compound of [the compound].

[0016] In some embodiments, the compound of formula (I) is formula (II-c) or (II-d): [ka] It is a compound of R. In some embodiments, 19 is -CH3. In some embodiments, R 7 is alkyl (e.g., unsubstituted alkyl or -CH2OR) A1 ) or -OR A1 In some embodiments, R 7 is -CH3, -CH2CH3, -OH, -OCH3, or -CH2OCH3. In some embodiments, R 17 is -OCH3, -CN, or -C(O)CH3. In some embodiments, R 17 is -C(O)CH2R C1 In some embodiments, R 17 is -C(O)CH2R B1 In some embodiments, R 17 These are alkoxy, cyano, or -C(O)R B1 That is. Some actual In terms of application form, R B1 is pyrazolyl (e.g., cyanosubstituted pyrazolyl). In some embodiments, R B1 is a tetrazolyl (e.g., a methyl-substituted tetrazolyl). In some embodiments, R B1is a bicyclic heteroaryl (e.g., a methoxy-substituted bicyclic heteroaryl). In some embodiments, R B1 teeth, [ka] In some embodiments, R B1 teeth, [ka] That is the case.

[0017] In some embodiments, R 6 is a halogen. In some embodiments, R 6 It is fluorine.

[0018] In some embodiments, R 11a and R 11b Each of these is independently hydrogen, a C1-C6 alkyl (e.g., a C1-C6 haloalkyl), a C1-C6 alkoxy (e.g., a C1-C6 alkoxyhalo), or -OH. In some embodiments, R 11a and R 11b They come together to form an oxo. In some embodiments, R 17 R is a C1-C6 alkoxy (e.g., -OCH3), cyano, or nitro. In some embodiments, R 19 This refers to hydrogen or substituted or unsubstituted C1-C6 alkyl groups (e.g., -CH2OR X , here R X (These are hydrogen, C1-C6 alkyl, or C1-C6 alkoxy.)

[0019] In some embodiments, the compound of formula (I) is formula (III-a) or (III-b): [ka] A compound wherein in formula (III-a) or (III-b), Ra is hydrogen, halogen, C1-C6 alkyl (e.g., -CH3), or -OH. In some embodiments, the compound of formula (I) is of formula (IV-a) or (IV-b):

Chemical formula

[0020] In one aspect, provided is a compound of formula (V):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0021] In some embodiments, R 3 It is alkyl.

[0022] In some embodiments, the compound of formula (V) is formula (Va) or (Vb): [ka] It is a compound of R. In some embodiments, 2 , R 4 , R 6 , R 11a , and R 11b Each of them is independently hydrogen. In some embodiments, R 2 , R 4 , R 6 , R 11a , and R 11b These are all hydrogen. In some embodiments, R 2 , R 4 , and R 6Each of these is independently a halogen, a C1-C6 alkyl, a C1-C6 alkoxy, or -OH. In some embodiments, R 3 is a C1-C6 alkyl group (e.g., C1-C6 haloalkyl or -CH3). In some embodiments, the compound of formula (V) is formula (VI-a) or (VI-b): [ka] It is a compound of formula (V). In some embodiments, the compound of formula (V) is formula (VI-c) or (VI-d): [ka] It is a compound of R. In some embodiments, 19 is -CH3. In some embodiments, R 12 is -OR A1 In some embodiments, R 12 is -CH3, -CH2CH3, -OH, -OCH3, or -CH2OCH3. In some embodiments, R 17 is -OCH3, -CN, or -C(O)CH3. In some embodiments, R 17 is -C(O)CH2R C1 In some embodiments, R 17 is -C(O)CH2R B1 In some embodiments, R 17 These are alkoxy, cyano, or -C(O)R B1 That is the case.

[0023] In some embodiments, R B1 is pyrazolyl (e.g., cyanosubstituted pyrazolyl). In some embodiments, R B1 is a tetrazolyl (e.g., a methyl-substituted tetrazolyl). In some embodiments, R B1 is a bicyclic heteroaryl (e.g., a methoxy-substituted bicyclic heteroaryl). In some embodiments, R B1 teeth, [ka] In some embodiments, R B1 teeth, [ka] That is the case.

[0024] In some embodiments, R 6 is a halogen. In some embodiments, R 6 It is fluorine.

[0025] In some embodiments, R 11a and R 11b Each of these is independently hydrogen, a C1-C6 alkyl (e.g., a C1-C6 haloalkyl), a C1-C6 alkoxy (e.g., a C1-C6 haloalkoxy), or -OH. In some embodiments, R 11a and R 11b They come together to form an oxo. In some embodiments, R 17 is a C1-C6 alkoxy (e.g., -OCH3) or cyano. In some embodiments, R 19 This refers to hydrogen or substituted or unsubstituted C1-C6 alkyl groups (e.g., -CH2OR X , here R X (wherein is hydrogen, C1-C6 alkyl, or C1-C6 alkoxy). In some embodiments, the compound of formula (V) is formula (VII-a) or (VII-b): [ka] It is a compound of, In equation (VII-a) or (VII-b), R a is hydrogen, halogen, C1-C6 alkyl (e.g., -CH3), or -OH. In some embodiments, the compound of formula (V) is formula (VIII-a) or (VIII-b): [ka] A compound of, In equation (VIII-a) or (VIII-b), m is 0, 1, or 2, and n is 0, 1, or 2, R b Each of them is independently hydrogen, a halogen, or a C1-C6 alkyl; R c Each of these is independently a halogen, a C1-C6 alkyl (e.g., -CH3 or C1-C6 haloalkyl), a C1-C6 alkoxy, a cyano, or an -OH group.

[0026] In some embodiments, A is a 5- to 10-membered ring. In some embodiments, A is a fused bicyclic ring. In some embodiments, A is a monocyclic heteroaryl or bicyclic heteroaryl.

[0027] In one aspect, the formula (IX) provided herein is: [ka] A compound of or a pharmaceutically acceptable salt thereof, in formula (IX), [ka] It represents a single or double bond, as far as the valence allows; R 2 , R 4 , R 6 , R 11a , and R 11b Each of these is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocykryl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 And here R A1Each example is independently either a hydrogen atom, alkyl atom, alkenyl atom, alkynyl atom, carbocykyl atom, heterocyclyl atom, aryl atom, heteroaryl atom, 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, or two R atoms. A1 The groups bond to form a heterocyclic or heteroaryl ring; R A2 is alkyl, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, or heteroaryl; or R 11a and R 11b They come together to form an oxo; R 3 These are hydrogen, alkyl, alkenyl, alkynyl, carbocykrill, heterocyclyl, aryl, or heteroaryl; R 5 It either does not exist or is hydrogen; [ka] represents a single bond or a double bond, where at the site [ka] If one of them is a double bond, the other [ka] It is a single bond; [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 17 These are alkoxy, cyano, nitro, aryl, heteroaryl, and -C(O)R B1 -C(O)CH2R B1, or -C(O)CH2CH2R B1 And here R B1 is hydrogen, -OH, -N(R A1 )2, alkoxy, aryl, or heteroaryl; R 19 is hydrogen or alkyl; R 16 These include halogens, cyano, nitro, alkyl, alkenyl, alkynyl, carbocykryl, heterocyclyl, aryl, heteroaryl, and -OR. A1 , -SR A1 , -N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 It is a compound or a pharmaceutically acceptable salt thereof.

[0028] In some embodiments, R 3 It is an alkyl group.

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

[0030] In some embodiments, R 2 , R 4 , and R 6 , R 11a , and R 11b Each of them is independently hydrogen. In some embodiments, R 2 , R 4 , and R 6 , R 11a ,oh Call R 11b all are hydrogen. In some embodiments, R 2 , R 4 , and R 6Each of these is independently a halogen, a C1-C6 alkyl, a C1-C6 alkoxy, or an -OH group.

[0031] In some embodiments, R 3 This is a C1-C6 alkyl group (for example, a C1-C6 haloalkyl group or -CH3 group).

[0032] In some embodiments, the compound of formula (IX) is formula (Xa) or (Xb): [ka] It is a compound of [the compound].

[0033] In some embodiments, the compound of formula (IX) is formula (Xc) or (Xd): [ka] It is a compound of [the compound].

[0034] In some embodiments, R 19 is -CH3. In some embodiments, R 16 is alkyl or -OR A1 In some embodiments, R 16 is -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2. In some embodiments, R 17 is -OCH3, -CN, or -C(O)CH3. In some embodiments, R 17 is -C(O)CH2R C1 In some embodiments, R 17 is -C(O)CH2R B1 In some embodiments, R 17 These are alkoxy, cyano, or -C(O)R B1 In some embodiments, R B1 is pyrazolyl (e.g., cyanosubstituted pyrazolyl). In some embodiments, R B1 is a tetrazolyl (e.g., a methyl-substituted tetrazolyl). In some embodiments, R B1is a bicyclic heteroaryl (e.g., a methoxy-substituted bicyclic heteroaryl). In some embodiments, R B1 teeth, [ka] In some embodiments, R B1 teeth, [ka] That is the case.

[0035] In some embodiments, R 6 is a halogen. In some embodiments, R 6 It is fluorine.

[0036] In some embodiments, R 11a and R 11b Each of these is independently hydrogen, a C1-C6 alkyl (e.g., a C1-C6 haloalkyl), a C1-C6 alkoxy (e.g., a C1-C6 haloalkoxy), or -OH. In some embodiments, R 11a and R 11b They come together to form an oxo.

[0037] In some embodiments, R 17 The group is a C1-C6 alkoxy (e.g., -OCH3), cyano, or nitro group.

[0038] In some embodiments, R 19 This refers to hydrogen or substituted or unsubstituted C1-C6 alkyl groups (e.g., -CH2OR X , here R X (These are hydrogen, C1-C6 alkyl, and C1-C6 alkoxy.)

[0039] In some embodiments, the compound of formula (IX) is of formula (X- a1 ) or (X- b1 ): [ka] A compound of, Formula(X- a1 ) or (X- b1 ) in R a The group is hydrogen, a halogen, a C1-C6 alkyl group (e.g., -CH3), or an -OH group.

[0040] In some embodiments, the compound of formula (IX) is formula (XI-a) or (XI-b): [ka] A compound of, In equation (XI-a) or (XI-b), m is 0, 1, or 2, and n is 0, 1, or 2, R b Each of them is independently hydrogen, halogen, or C1-C6 alkyl, and R c Each of these is independently a halogen, a C1-C6 alkyl (e.g., -CH3 or C1-C6 haloalkyl), a C1-C6 alkoxy, a cyano, or an -OH group.

[0041] In some embodiments, A is a 5- to 10-membered ring. In some embodiments, A is a fused bicyclic ring. In some embodiments, A is a monocyclic heteroaryl or bicyclic heteroaryl.

[0042] In one aspect, compounds listed in Table 1 or pharmaceutically acceptable salts thereof are also provided herein.

[0043] In one aspect, a pharmaceutical composition comprising a compound described herein (for example, a compound of formula (I), formula (V), or formula (IX)) and a pharmaceutically acceptable excipient is provided herein.

[0044] In one aspect, a method for inducing sedation and / or anesthesia in a subject is provided herein, the method comprising administering to the subject an effective amount of one of the compounds described herein (e.g., a compound of formula (I), formula (V), or formula (IX)) or a pharmaceutically acceptable salt thereof.

[0045] In one phase, an effective amount of the compounds described herein (e.g., formula (I), formula (V) Methods for administering to a subject requiring administration of a pharmaceutically acceptable salt thereof (1), (2), or a compound of formula (IX), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof, are provided herein, wherein the subject experiences sedation and / or anesthesia within 2 hours of administration. In some embodiments, the subject experiences sedation and / or anesthesia within 1 hour of administration. In some embodiments, the subject experiences sedation and / or anesthesia immediately. In some embodiments, the compound is administered by intravenous administration. In some embodiments, the compound is administered chronically.

[0046] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0047] In some embodiments, the compound is administered in combination with another therapeutic agent.

[0048] In one instance, a method for treating a seizure in a subject is provided herein, which comprises administering to the subject an effective amount of one of the compounds described herein (for example, a compound of formula (I), formula (V), or formula (IX)).

[0049] In one aspect, a method for treating epilepsy or status epilepticus in a subject is provided herein, the method comprising administering to the subject an effective amount of a compound described herein (for example, a compound of formula (I), formula (V), or formula (IX)).

[0050] In one aspect, a method for treating a neuroendocrine disorder or dysfunction in a subject is provided herein, the method comprising administering to the subject an effective amount of a compound described herein (for example, a compound of formula (I), formula (V), or formula (IX)).

[0051] In one aspect, a method for treating a neurodegenerative disease or disorder in a subject is provided herein, the method comprising administering to the subject an effective amount of a compound described herein (for example, a compound of formula (I), formula (V), or formula (IX)).

[0052] In one aspect, a method for treating a motor disorder or tremor in a subject is provided herein, the method comprising administering to the subject an effective amount of a compound described herein (for example, a compound of formula (I), formula (V), or formula (IX)).

[0053] In one aspect, a method for treating a mood disorder or anxiety disorder in a subject is provided herein, the method comprising administering to the subject an effective amount of a compound described herein (for example, a compound of formula (I), formula (V), or formula (IX)).

[0054] In one aspect, a method for treating a GABA function-related disorder in a subject requiring treatment of such disorder is provided herein, the method comprising administering to the subject a therapeutically effective amount of one of the compounds described herein (e.g., a compound of formula (I), formula (V), or formula (IX)), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of the compound thereof.

[0055] In one aspect, a kit is provided herein comprising a solid composition containing a compound described herein (for example, a compound of formula (I), formula (V), or formula (IX)) and a sterile diluent.

[0056] Therefore, in another context, a method is provided for treating a CNS-related disorder in a subject requiring treatment of the CNS-related disorder, the method comprising administering to the subject an effective amount of one of the compounds described herein (for example, a compound of formula (I), formula (V), or formula (IX)). This includes the following. In certain embodiments, CNS-related disorders are selected from the group consisting of 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, and tinnitus. In certain embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered chronically. In certain embodiments, the compound is administered continuously, for example, by continuous intravenous infusion.

[0057] In some embodiments, the subject is a subject having Rett syndrome, Fragile X syndrome, or Angelman syndrome. In certain embodiments, for example, the following are provided: (Item 1) Equation (I): [ka] A compound of or a pharmaceutically acceptable salt thereof, in formula (I), [ka] It represents a single or double bond, as far as the valence allows; R 2 , R 4 , R 6 , R 11a , and R 11b Each of these is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocykryl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 And here R A1Each example is independently either a hydrogen atom, alkyl atom, alkenyl atom, alkynyl atom, carbocykyl atom, heterocyclyl atom, aryl atom, heteroaryl atom, 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, or two R atoms. A1 The groups bond to form a heterocyclic or heteroaryl ring; R A2 is alkyl, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, or heteroaryl; or R 11a and R 11b They come together to form an oxo; R 3 These are hydrogen, alkyl, alkenyl, alkynyl, carbocykrill, heterocyclyl, aryl, or heteroaryl; R 5 It either does not exist or is hydrogen; [ka] represents a single bond or a double bond, where at the site [ka] If one of them is a double bond, the other [ka] It is a single bond; [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 17 These are alkoxy, cyano, nitro, aryl, heteroaryl, or -C(O)R B1 -C(O)CH2R B1 , or -C(O)CH2CH2R B1And here R B1 is hydrogen, -OH, alkoxy, aryl, or heteroaryl; R 19 is hydrogen or alkyl; R 7 These include halogens, cyano, nitro, alkyl, alkenyl, alkynyl, carbocykryl, heterocyclyl, aryl, heteroaryl, and -OR. A1 , -SR A1 , -N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 A compound or a pharmaceutically acceptable salt thereof. (Item 2) The compound of formula (I) is formula (Ia) or (Ib): [ka] The compound described in item 1, which is a compound of the above. (Item 3) R 2 , R 4 , and R 6 , R 11a , and R 11b Each of the compounds listed in item 2 is independently a hydrogen atom. (Item 4) R 2 , R 4 , R 6 , R 11a , and R 11b These are compounds listed in item 2, all of which are hydrogen. (Item 5) R 2 , R 4 , and R 6 Each of the compounds listed in item 2 is independently a halogen, a C1-C6 alkyl, a C1-C6 alkoxy, or an -OH group. (Item 6) R 3The compound is a C1-C6 alkyl (e.g., C1-C6 haloalkyl or -CH3) as described in item 2. (Item 7) The compound of formula (I) is of formula (II-a) or (II-b): [ka] The compound described in item 2. (Item 8) The compound of formula (I) is of formula (II-c) or (II-d): [ka] The compound described in item 2. (Item 9) R 19 This is a compound listed in item 8, which is -CH3. (Item 10) R 7 The compounds listed in item 8, which are -CH3, -CH2CH3, -OH, -OCH3, or -CH2OCH3. (Item 11) R 17 The compounds listed in item 8 are -OCH3, -CN, or -C(O)CH3. (Item 12) R 17 is -C(O)CH2R C1 The compound described in item 8. (Item 13) R 17 is -C(O)CH2R B1 The compound described in item 8. (Item 14) R 17 These are alkoxy, cyano, or -C(O)R B1 The compound described in item 8. (Item 15) R B1 The compound is pyrazolyl (e.g., cyanosubstituted pyrazolyl), as described in item 8. (Item 16) R B1The compound is a tetrazolyl (e.g., methyl-substituted tetrazolyl), as described in item 8. (Item 17) R B1 The compound is a bicyclic heteroaryl (e.g., a methoxy-substituted bicyclic heteroaryl), as described in item 8. (Item 18) R B1 teeth, [ka] The compound described in item 8. (Item 19) R B1 teeth, [ka] The compound described in item 8. (Item 20) R 6 This is a halogen, a compound listed in item 2. (Item 21) R 6 The compound is fluorine, as described in item 2. (Item 22) R 11a and R 11b Each of the compounds described in item 2 is independently a hydrogen atom, a C1-C6 alkyl group (e.g., a C1-C6 haloalkyl group), a C1-C6 alkoxy group (e.g., a C1-C6 alkoxyhalo group), or an OH group. (Item 23) R 11a and R 11b These compounds combine to form an oxo, as described in item 2. (Item 24) R 17 The compounds listed in item 2 are C1-C6 alkoxy (e.g., -OCH3), cyano, or nitro. (Item 25) R 19 This refers to hydrogen or substituted or unsubstituted C1-C6 alkyl groups (e.g., -CH2OR X , here R XThe compounds listed in item 2, which are hydrogen, C1-C6 alkyl, or C1-C6 alkoxy. (Item 26) The compound of formula (I) is of formula (IV-a) or (IV-b): [ka] A compound listed in item 2, which is a compound of the following: In equation (IV-a) or (IV-b), m is 0, 1, or 2; n is 0, 1, or 2; R b Each of them is independently hydrogen, a halogen, or a C1-C6 alkyl group; R c A compound in which each of the elements is independently a halogen, a C1-C6 alkyl (e.g., -CH3 or C1-C6 haloalkyl), a C1-C6 alkoxy, a cyano, or an -OH group. (Item 27) The compound of formula (I) is formula (III-a) or (III-b): [ka] A compound listed in item 2, which is a compound of formula (III-a) or (III-b), where R a A compound is a hydrogen, halogen, C1-C6 alkyl (e.g., -CH3), or -OH group. (Item 28) The compound of formula (I) is of formula (IV-a) or (IV-b): [ka] A compound described in item 2, which is a compound of formula (IV-a) or (IV-b), m is 0, 1, or 2; n is 0, 1, or 2; R b Each of them is independently hydrogen, a halogen, or a C1-C6 alkyl group; R cA compound in which each of the elements is independently a halogen, a C1-C6 alkyl (e.g., -CH3 or C1-C6 haloalkyl), a C1-C6 alkoxy, a cyano, or an -OH group. (Item 29) A is a compound described in item 15, having a 5-10 membered ring. (Item 30) A is a compound described in item 15, which is a fused bicyclic ring. (Item 31) A is a compound as described in item 15, which is a monocyclic heteroaryl or bicyclic heteroaryl. (Item 32) Formula (V): [ka] A compound or a pharmaceutically acceptable salt thereof In equation (V), [ka] It represents a single or double bond, as far as the valence allows; R 2 , R 4 , R 6 , R 11a , and R 11b Each of these is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocykryl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 And here R A1 Each example is independently either a hydrogen atom, alkyl atom, alkenyl atom, alkynyl atom, carbocykyl atom, heterocyclyl atom, aryl atom, heteroaryl atom, 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, or two R atoms. A1The groups bond to form a heterocyclic or heteroaryl ring; R A2 is alkyl, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, or heteroaryl; or R 11a and R 11b They come together to form an oxo; R 3 These are hydrogen, alkyl, alkenyl, alkynyl, carbocykrill, heterocyclyl, aryl, or heteroaryl; R 5 It either does not exist or is hydrogen; [ka] represents a single bond or a double bond, where at the site [ka] If one of them is a double bond, the other [ka] It is a single bond; [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 17 These are alkoxy, cyano, nitro, aryl, heteroaryl, -C(O)R B1 -C(O)CH2R B1 , or -C(O)CH2CH2R B1 And here R B1 is hydrogen, -OH, alkoxy, aryl, or heteroaryl; R 19 is hydrogen or alkyl; R 12These include halogens, cyano, nitro, alkyl, alkenyl, alkynyl, carbocykryl, heterocyclyl, aryl, heteroaryl, and -OR. A1 , -SR A1 , -N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 A compound or a pharmaceutically acceptable salt thereof. (Item 33) The compound of formula (V) is formula (Va) or (Vb): [ka] The compound described in item 32, which is a compound of the above. (Item 34) R 2 , R 4 , R 6 , R 11a , and R 11b Each of the compounds described in item 33 is independently hydrogen. In some embodiments, R 2 , R 4 , R 6 , R 11a , and R 11b It is all hydrogen. (Item 35) R 2 , R 4 , and R 6 Each of the compounds listed in item 33 is independently a halogen, a C1-C6 alkyl, a C1-C6 alkoxy, or an -OH group. (Item 36) R 3 The compound is a C1-C6 alkyl (e.g., C1-C6 haloalkyl or -CH3) as described in item 33. (Item 37) The compound of formula (V) is of formula (VI-a) or (VI-b): [ka] The compound described in item 33, which is a compound of the above. (Item 38) The compound of formula (V) is of formula (VI-c) or (VI-d): [ka] The compound described in item 33, which is a compound of the above. (Item 39) R 19 This is a compound listed in item 38, which is -CH3. (Item 40) R 7 The compounds listed in item 38, which are -CH3, -CH2CH3, -OH, -OCH3, or -CH2OCH3. (Item 41) R 17 The compounds listed in item 38, which are -OCH3, -CN, or -C(O)CH3. (Item 42) R 17 is -C(O)CH2R C1 The compound described in item 38. (Item 43) R 17 is -C(O)CH2R B1 The compound described in item 38. (Item 44) R 17 These are alkoxy, cyano, or -C(O)R B1 The compound described in item 38. (Item 45) R B1 The compound is pyrazolyl (e.g., cyanosubstituted pyrazolyl), as described in item 38. (Item 46) R B1 The compound is tetrazolyl (e.g., methyl-substituted tetrazolyl), as described in item 38. (Item 47) R B1 The compound is a bicyclic heteroaryl (e.g., a methoxy-substituted bicyclic heteroaryl), as described in item 38. (Item 48) R B1teeth, [ka] The compound described in item 38. (Item 49) R B1 teeth, [ka] The compound described in item 38. (Item 50) R 6 This is a halogen, a compound listed in item 33. (Item 51) R 6 This is fluorine, a compound listed in item 33. (Item 52) R 11a and R 11b Each of the compounds described in item 33 is independently hydrogen, a C1-C6 alkyl (e.g., a C1-C6 haloalkyl), a C1-C6 alkoxy (e.g., a C1-C6 haloalkoxy), or -OH. In some embodiments, R 11a and R 11b They come together to form an oxo. (Item 53) R 17 The compound is a C1-C6 alkoxy (e.g., -OCH3) or cyano compound as described in item 33. (Item 54) R 19 This refers to hydrogen or substituted or unsubstituted C1-C6 alkyl groups (e.g., -CH2OR X , here R X The compounds listed in item 33, which are hydrogen, C1-C6 alkyl, or C1-C6 alkoxy. (Item 55) The compound of formula (V) is of formula (VII-a) or (VII-b): [ka] A compound described in item 33, which is a compound of the following: In equation (VII-a) or (VII-b), R a A compound is a hydrogen, halogen, C1-C6 alkyl (e.g., -CH3), or -OH group. (Item 56) The compound of formula (V) is of formula (VIII-a) or (VIII-b): [ka] A compound described in item 33, which is a compound of the following: In equation (VIII-a) or (VIII-b), m is 0, 1, or 2, and n is 0, 1, or 2, R b Each of them is independently hydrogen, a halogen, or a C1-C6 alkyl; R c A compound in which each of the elements is independently a halogen, a C1-C6 alkyl (e.g., -CH3 or C1-C6 haloalkyl), a C1-C6 alkoxy, a cyano, or an -OH group. (Item 57) A is a compound as described in item 33, which is a 5- to 10-membered ring. In some embodiments, A is a fused bicyclic ring. In some embodiments, A is a monocyclic heteroaryl or bicyclic heteroaryl. (Item 58) Formula (IX): [ka] A compound of or a pharmaceutically acceptable salt thereof, in formula (IX), [ka] It represents a single or double bond, as far as the valence allows; R 2 , R 4 , R 6 , R 11a , and R 11b Each of these is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocykryl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1, -N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 And here R A1 Each example is independently either a hydrogen atom, alkyl atom, alkenyl atom, alkynyl atom, carbocykyl atom, heterocyclyl atom, aryl atom, heteroaryl atom, 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, or two R atoms. A1 The groups bond to form a heterocyclic or heteroaryl ring; R A2 is alkyl, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, or heteroaryl; or R 11a and R 11b They come together to form an oxo; R 3 These are hydrogen, alkyl, alkenyl, alkynyl, carbocykrill, heterocyclyl, aryl, or heteroaryl; R 5 It either does not exist or is hydrogen; [ka] represents a single bond or a double bond, where at the site [ka] If one of them is a double bond, the other [ka] It is a single bond; [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 17 These are alkoxy, cyano, nitro, aryl, heteroaryl, and -C(O)R B1 -C(O)CH2R B1 , or -C(O)CH2CH2R B1 And here R B1 is hydrogen, -OH, -N(R A1 )2, alkoxy, aryl, or heteroaryl; R 19 is hydrogen or alkyl; R 16 These include halogens, cyano, nitro, alkyl, alkenyl, alkynyl, carbocykryl, heterocyclyl, aryl, heteroaryl, and -OR. A1 , -SR A1 , -N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 A compound or a pharmaceutically acceptable salt thereof. (Item 59) The compound of formula (IX) is formula (IX-a) or (IX-b): [ka] A compound of the compound listed in item 58. (Item 60) R 2 , R 4 , and R 6 , R 11a , and R 11b Each of the compounds described in item 59 is independently hydrogen. In some embodiments, R 2 , R 4 , and R 6 , R 11a , and R 11b all are hydrogen. In some embodiments, R 2 , R 4 , and R6 Each of these is independently a halogen, a C1-C6 alkyl, a C1-C6 alkoxy, or an -OH group. (Item 61) R 3 The compound is a C1-C6 alkyl (e.g., C1-C6 haloalkyl or -CH3) as described in item 59. (Item 62) The compound of formula (IX) is formula (Xa) or (Xb): [ka] A compound of the compound described in item 59. (Item 63) The compound of formula (IX) is formula (Xc) or (Xd): [ka] A compound of the compound described in item 59. (Item 64) R 19 This is a compound listed in item 63, which is -CH3. (Item 65) R 7 The compounds listed in item 63, which are -CH3, -CH2CH3, -OH, -OCH3, or -CH2OCH3. (Item 66) R 17 The compounds listed in item 63 are -OCH3, -CN, or -C(O)CH3. (Item 67) R 17 is -C(O)CH2R C1 The compound described in item 63. (Item 68) R 17 is -C(O)CH2R B1 The compound described in item 63. (Item 69) R 17 These are alkoxy, cyano, or -C(O)R B1 The compound described in item 63. (Item 70) RB1 The compound is pyrazolyl (e.g., cyanosubstituted pyrazolyl), as described in item 63. (Item 71) R B1 The compound is tetrazolyl (e.g., methyl-substituted tetrazolyl), as described in item 63. (Item 72) R B1 The compound is a bicyclic heteroaryl (e.g., a methoxy-substituted bicyclic heteroaryl), as described in item 63. (Item 73) R B1 teeth, [ka] The compound described in item 63. (Item 74) R B1 teeth, [ka] The compound described in item 63. (Item 75) R 6 is a halogen, as described in item 58. In some embodiments, R 6 It is fluorine. (Item 76) R 11a and R 11b Each of the compounds described in item 58 is independently hydrogen, a C1-C6 alkyl (e.g., a C1-C6 haloalkyl), a C1-C6 alkoxy (e.g., a C1-C6 haloalkoxy), or -OH. In some embodiments, R 11a and R 11b They come together to form an oxo. (Item 77) R 17 The compounds listed in item 58 are C1-C6 alkoxy (e.g., -OCH3), cyano, or nitro. (Item 78) R 19 This refers to hydrogen or substituted or unsubstituted C1-C6 alkyl groups (e.g., -CH2ORX , here R X Compounds listed in item 58 (which are hydrogen, C1-C6 alkyl, or C1-C6 alkoxy). (Item 79) The compound of formula (IX) is formula (Xa) or (Xb): [ka] A compound described in item 58, which is a compound of the following: In equation (Xa) or (Xb), R a A compound is a hydrogen, halogen, C1-C6 alkyl (e.g., -CH3), or -OH group. (Item 80) The compound of formula (IX) is formula (XI-a) or (XI-b): [ka] A compound described in item 58, which is a compound of the following: In equation (XI-a) or (XI-b), m is 0, 1, or 2, and n is 0, 1, or 2, R b Each of them is independently hydrogen, halogen, or C1-C6 alkyl, and R c A compound in which each of the elements is independently a halogen, a C1-C6 alkyl (e.g., -CH3 or C1-C6 haloalkyl), a C1-C6 alkoxy, a cyano, or an -OH group. (Item 81) A is a compound as described in item 58, which is a 5- to 10-membered ring. In some embodiments, A is a fused bicyclic ring. In some embodiments, A is a monocyclic heteroaryl or bicyclic ring. It is a cyclic heteroaryl. (Item 82) [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] A compound selected from the group consisting of the following. (Item 83) [ka]

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[0058] 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 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; Smith and March, March's Advanced Organic 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.

[0059] Isomers (e.g., stereoisomers) are formed by methods known to those skilled in the art (chiral high-pressure liquid chromatography (HPLC), supercritical fluid chromatography (SFC), and the formation of chiral salts). They can be isolated from the mixture by means of (including crystallization); or preferred isomers can be prepared by asymmetric synthesis. For example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (ELEliel, editor, Univ. of See 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.

[0060] The absolute configuration of a chiral center can be determined using methods known to those skilled in the art. In some embodiments, the absolute configuration of a chiral center of a compound can be elucidated from the X-ray single crystal structure of the compound. In some embodiments, the absolute configuration of a chiral center elucidated from the X-ray crystal structure of a compound can be used to determine the corresponding absolute configuration of a chiral center in another compound obtained from the same or similar synthesis method. In some embodiments, the absolute configuration of a chiral center can be determined using nuclear magnetic resonance (NMR) spectroscopy (e.g., by nuclear Overhauser effect (NOE) experiments).

[0061] 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.

[0062] 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-compound may, for example, contain about 90% excipients and about 10% enantiomerically pure R-compound. 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, based on 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-compound. 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, based on 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.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] "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 8 carbon atoms ("C"). 1~8 "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. do ("C 2~6 Alkyl). C 1~6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), 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).

[0067] "Alkenyl" refers to a radical of a linear or branched hydrocarbon group having 2 to 20 carbon atoms and one or more carbon-carbon double bonds, but no carbon-carbon triple bonds ("C"). 2~20This refers to an alkenyl group. 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 8 carbon atoms ("C"). 2~8 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C"). 2~6 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C"). 2~5 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C"). 2~4 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C"). 2~3 "Alkenyl"). In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). One or more carbon-carbon double bonds may be located internally (e.g., 2-butenyl) or at the terminal (e.g., 1-butenyl). C 2~4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), and butadienyl. (C4) is one example. 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.

[0068] "Alkynyl" refers to a radical of a linear or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more double bonds. 2~20 This refers to an "alkynyl" group. 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 8 carbon atoms ("C"). 2~8 ("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 Alkinil). Part In the embodiment, the alkynyl group has 2 to 3 carbon atoms ("C 2~3 "Alkynyl"). In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). One or more carbon-carbon triple bonds may be located internally (e.g., 2-butynyl) or at the terminal (e.g., 1-butynyl). C 2~4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), and 2-butynyl (C4). 2~6 An example of an alkenyl group is the aforementioned C 2~4 Examples include alkynyl groups, as well as pentynyl (C5), hexynyl (C6), and the like. Further examples of alkynyls include heptynyl (C7), octinyl (C8), and the like. Unless otherwise specified, each presence of an alkynyl group 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 C2~10 It is an alkynyl group. In certain embodiments, the alkynyl group is a substituted C 2~10 It is alkinyl.

[0069] "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 carbocyclyl 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. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each presence of an aryl group is independently substituted as necessary, i.e., unsubstituted ("unsubstituted aryl") or with one or more substituents. It is substituted with ("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.

[0070] 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 groups.

[0071] 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 , C Major League 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.

[0072] Other representative aryl groups that have condensed heterocyclyl groups include the following: [ka] These are listed, and here each W is C(R 66 )2, NR 66 Selected from , O, and S; and each Y is carbonyl, NR 66 , selected from O and S; and R 66 These are independently hydrogen, C1-C8 alkyl, and C3-C 10 Cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 These are aryls and heteroaryls with 5 to 10 members.

[0073] Unless otherwise stated, “halo” or “halogen” means a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom, either independently or as part of another substituent. The term “halide” means a fluoride, chloride, bromide, or iodide atom, either by itself or as part of another substituent. In certain embodiments, the halo group is either fluorine or chlorine.

[0074] "Haloalkyl" and "haloalkoxy" may include alkyl and alkoxy structures substituted with one or more halo groups or combinations thereof. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, where the halo is fluorine.

[0075] Unless otherwise stated, "hydroxy" or "hydroxyl" refers to the -OH group, either independently or as part of another substituent.

[0076] "Hydroxyalkyl" or "hydroxylalkyl" may include alkyl structures substituted with one or more hydroxyl groups.

[0077] "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. For bicyclic heteroaryl groups that do not contain heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.), the bond site may be located on either the heteroatom-containing ring (e.g., 2-indolyl) or the heteroatom-free ring (e.g., 5-indolyl).

[0078] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system in which a ring carbon atom and 1-4 ring heteroatoms are provided to the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system in which a ring carbon atom and 1-4 ring heteroatoms are provided to the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system in which a ring carbon atom and 1-4 ring heteroatoms are provided to the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl group has one or two ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heteroaryl group has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each presence of a heteroaryl group is independently substituted as necessary, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0079] 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.

[0080] A typical example of a heteroaryl is the following equation: [ka] These are listed, where each Y is a carbonyl, N, or NR.65 Selected from O and S; R 65 These are independently hydrogen, C1-C8 alkyl, and C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 They are aryl and 5- to 10-membered heteroaryls.

[0081] 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 Carbocyclyl group, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl ( Examples include, but are not limited to, 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 carbocyclyl. In a particular embodiment, carbocyclyl The lyl group is a substituted C 3~10 It is carbocyclyl.

[0082] 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.

[0083] 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.

[0084] 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 heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclil has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclil has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0085] 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.

[0086] Specific examples of heterocyclyl groups are shown in the following illustrative examples: [ka] Here, each W is CR 67 , C(R 67 )2, NR 67 Selected from O and S; each Y is NR 67 Selected from O and S; R 67 These are independently hydrogen, C1-C8 alkyl, and C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 These are aryl and 5-10 membered heteroaryl rings. These heterocyclyl rings include acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (e.g., amide), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azide, and carbo. The substituents may be substituted as needed with one or more groups selected from xyl, cyano, cycloalkyl, halogen, hydroxy, keto, nitro, thiol, -S-alkyl, -S-aryl, -S(O)-alkyl, -S(O)-aryl, -S(O)2-alkyl, and -S(O)2-aryl. The substituents include carbonyl or thiocarbonyl groups, which provide, for example, lactam derivatives and urea derivatives.

[0087] "Ashil" is -C(O)R 20 It refers to a radical, and here, R 20This includes hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl, as defined herein. "Alkanoyl" is R 20 The 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).

[0088] "Acylamino" means -NR 22 C(O)R 23 It refers to a radical, and here, R 22 and R 23Each presence independently includes hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl, as defined herein, or R 22 This is an amino protecting group. Examples of "acylamino" groups include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino, and benzylcarbonylamino. Specific example of "acylamino" groups are -NR 24 C(O)-C1~C8 alkyl, -NR 24 C(O)-(CH2) t (C6~C 10 Ariel), -NR 24 C(O)-(CH2) t (5-10 member heteroaryl), -NR 24 C(O)-(CH2) t (C3~C 10 Cycloalkyl) and -NR 24 C(O)-(CH2) t (4-10 member heterocyclyl), where t is an integer from 0 to 4, and each R 24 R independently represents hydrogen or a C1-C8 alkyl group. In a particular embodiment, R 25 C1-C8 alkyl groups substituted with H, halo, or hydroxyl; C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 These are aryl, arylalkyl, 5-10 member 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 hydroxyl; R 26 C1-C8 alkyl groups substituted with H, halo, or hydroxyl; C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10These are aryl, arylalkyl, 5-10 member 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; however, R 25 and R 26 fewer One of them is something other than H.

[0089] "Acyloxy" is -OC(O)R 27 It refers to a radical, and here, R 27 R 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, as defined herein. Typical examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, and benzylcarbonyl. In certain embodiments, R 28 These are C1-C8 alkyl groups substituted with halo or hydroxyl; 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 hydroxyl.

[0090] "alkoxy" means -OR 29 It refers to the base, and here, R 29These 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.

[0091] 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, hydroxy, 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) tExamples 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.

[0092] "Amino" refers to the -NH2 radical.

[0093] "Substituting amino acid" refers to the compound of the formula -N(R 38 ) refers to the amino group of 2, where R 38 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, a substituted or unsubstituted heteroaryl group, or an amino protecting group, where R 38 At least one of them is not hydrogen. In a particular embodiment, each R 38 These are independently hydrogen, C1-C8 alkyl, C3-C8 alkenyl, and C3 ~C8 Alkinyl, 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) tSelected from (4-10 member heterocyclyl), 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 link together to form an alkylene group.

[0094] Examples of "substituted amino" groups include -NR 39 -C1~C8 alkyl, -NR 39 -(CH2) t (C6~C 10 Ariel), -NR 39 -(CH2) t (5-10 member heteroaryl), -NR 39 -(CH2) t (C3~C 10 Cycloalkyl) and -NR 39 -(CH2) t Examples include (4-10 member heterocyclyls), but are not limited to these, where t is an integer from 0 to 4, for example, 1 or 2, and each R 39 The group independently represents 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.

[0095] "Azide" refers to the -N3 radical.

[0096] "Carbamoyl" or "amide" refers to the -C(O)NH2 radical.

[0097] "Substituted carbamoyl" or "substituted amide" refers to -C(O)N(R 62 ) refers to two radicals, where each R 62 R is independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or an amino protecting group, where R 62 At least one of them is not hydrogen. In a particular embodiment, R 62 H, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryls, and 5-10 member heteroaryls; or C1-C8 alkyls substituted with halo or hydroxyl; or C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Selected from aryls or 5-10 member heteroaryls, 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; provided that at least one R 62 It is anything other than H.

[0098] "Carboxylate" refers to the -C(O)OH radical.

[0099] "Cyano" refers to the -CN radical.

[0100] "Oxo" refers to =O.

[0101] "Nitro" refers to the -NO2 radical.

[0102] "Ethenyl" refers to a substituted or unsubstituted -(C=C)- molecule. "Ethylene" refers to a substituted or unsubstituted -(CC)- molecule. "Ethynyl" refers to a -(C≡C)- molecule.

[0103] A "nitrogen-containing heterocyclyl" group refers to a 4- to 7-membered non-aromatic cyclic group containing at least one nitrogen atom, for example, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazine (e.g., N-methylpiperazine). Specific examples include azetidine, piperidone, and piperazone.

[0104] 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.

[0105] Examples of carbon atom substituents include halogens, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, and -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb -SH, -SR aa -SSR cc、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-S C(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2Raa -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 Perhaloalkyl, 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, carbocyryl, heterocyclyl, aryl, and heteroaryl group independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with the base; R aa Each of these beings is independent of C 1~10 Alkyl, C 1~10 Perhaloalkyl, 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 aaThe 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; R bb Each of these entities exists independently as hydrogen, -OH, and -OR. aa , -N(R cc )2, -CN, -C(=O)R aa -C(=O)N(R cc )2, -CO2R aa , -SO2R aa -C(=NR cc )OR aa -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc -SOR aa -C(=S)N(R cc )2, -C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1~10 Alkyl, C 1~10 Perhaloalkyl, 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; R cc Each of these entities independently contains hydrogen and C 1~10Alkyl, C 1~10 Perhaloalkyl, 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; 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, -NRff 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 e e )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1~6 alkyl, C 1~6 perhaloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 carbocyclic, 3 - to 10 - member heterocyclic, C 6~10 aryl, 5 - to 10 - member heteroaryl, selected from, where each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups; R ee each occurrence of which is independently selected from C 1~6 alkyl, C 1~6 perhaloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 carbocyclic, C 6~10 aryl, 3 - to 10 - member heterocyclic, and 3 - to 10 - member heteroaryl, selected from, where each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups; Rff Each entity is independently selected from hydrogen, C 1~6 alkyl, C 1~6 perhaloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 carbocyclic, 3- to 10-membered heterocyclic, C 6~10 aryl and 5- to 10-membered heteroaryl, or two R ff groups are linked to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups; R gg Each entity 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 1~6alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1~6 alkyl), -OC(=NH)(C 1~6 alkyl), -OC(=NH)OC 1~6 alkyl, -C(=NH)N(C 1~6 alkyl)2, -C(=NH)NH(C 1~6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1~6 alkyl)2, -OC(NH)NH(C 1~6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1~6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 alkyl), -SO2NH2, -SO2C 1~6 alkyl, -SO2OC 1~6 alkyl, -OSO2C 1~6 alkyl, -SOC 1~6 alkyl, -Si(C 1~6 alkyl)3, -OSi(C 1~6 alkyl)3-C(=S)N(C 1~6 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 perhaloalkyl, C 2~6 alkenyl, C 2~6Alkinyl, C 3~10 Carbocyclyl, C 6~10 These are aryls, 3-10 membered heterocyclines, and 5-10 membered heteroaryls; where X - It is a counterion.

[0106] 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 - Examples include sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.) and carboxylate ions (e.g., acetate, ethanolate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0107] Nitrogen atoms can be substituted or unsubstituted, wherever the bond valency allows, and may include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, and -OR. aa , -N(R cc )2, -CN, -C(=O)R aa -C(=O)N(R cc )2, -CO2R aa , -SO2R aa -C(=NR bb )R aa -C(=NR cc )OR aa -C(=NR cc )N(R cc )2, -SO2N(R cc)2, -SO2R cc , -SO2OR cc -SOR aa -C(=S)N(R cc )2, -C(=O)SR cc -C(=S)SR cc -P(=O)2R aa -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1~10 Alkyl, C 1~10 Perhaloalkyl, 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 heteroaryls, or two R atoms bonded to a nitrogen atom. cc The groups are linked together to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted with R aa , R bb , R cc and R dd This is as defined above.

[0108] 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(Rcc )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 5-14 membered heteroaryl groups, where alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl each independently have 0, 1, 2, 3, 4, or 5 R dd It is substituted with the base, and here R aa , R bb , R cc and R dd The amino protecting group is as defined herein. Amino protecting groups are well known in the art and are described in detail in *Protecting Groups in Organic Synthesis*, TW Greene and PGMWuts, 3rd edition, John Wiley & Sons, 1999 (incorporated herein by reference).

[0109] 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).

[0110] 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 is one example, but it is not limited to these, R aa , R bb , and R cc These are defined herein. Oxygen protecting groups are well known in the art and are described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGMWuts, 3rd edition, John Wiley & Sons, 1999 (incorporated herein by reference).

[0111] 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).

[0112] 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 Examples include those described in detail in *Groups in Organic Synthesis*, TW Greene and PGMWuts, 3rd edition, John Wiley & Sons, 1999 (as incorporated herein by reference).

[0113] These and other exemplary substituents are described in detail in the detailed description, examples, and claims. The present invention is not intended to be limited in any way by the exemplary enumeration of substituents described above.

[0114] Other definitions As used herein, the term “modulation” refers to the inhibition or synergistic effect of GABA receptor function. A “modulator” (e.g., a modulatory compound) may be, for example, a GABA receptor agonist, partial agonist, antagonist, or partial antagonist.

[0115] "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).

[0116] "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 non-toxic 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. See, for example, Berge et al., J. Pharm. Sci. (1977) 66(1):1-79.

[0117] A “solvate” refers to a form of compound that is associated with a solvent or water (also called a “hydrate”), usually by solvolysis. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, and acetic acid. The compounds of the present invention may be prepared, for example, in crystalline form and then solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric and non-stoichiometric solvates. In certain examples, solvates may be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. “Solvates” encompass both solution phases and isolateable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0118] "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."

[0119] A "tautomer" is a compound with interchangeable forms of a specific compound structure, where the displacement of hydrogen atoms and electrons varies. Therefore, the two structures can be in equilibrium through the movement of π electrons and atoms (usually H). For example, enols and ke Ton is a tautomer because it is 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 an acid or a base. Tautomerism can be relevant to obtaining the optimal chemical reactivity and biological activity of the compound of interest.

[0120] The “subjects” to which the administration is intended include, but are not limited to, human (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, e.g., mammals (e.g., primates (e.g., cynomolgus macaques, rhesus macaques), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs). In certain embodiments, the subject is human. In certain embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein.

[0121] Diseases, disorders, and conditions are used interchangeably in this specification.

[0122] As used herein, unless otherwise specified, the terms “treat,” “treating,” and “treatment” refer to actions taken while a subject is suffering from a particular disease, disorder, or condition that reduce the severity of the disease, disorder, or condition, or that delay or slow the progression of the disease, disorder, or condition ("therapeutic treatment"), and also refer to actions taken before a subject begins to suffer from a particular disease, disorder, or condition ("preventive treatment").

[0123] Generally, the "effective amount" of a compound is the amount needed to elicit a desired biological response, for example, CNS This refers to an amount sufficient to treat the associated disorder and sufficient to induce anesthesia or sedation. As will be understood by those skilled in the art, the effective amount of the compound of the present invention may vary depending on factors such as the desired biological 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. The effective amount includes both therapeutic and prophylactic treatments.

[0124] 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” may include an amount that improves the overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effect of another therapeutic agent.

[0125] As used herein, unless otherwise specified, “preventive dose” of a compound means an amount sufficient to prevent or prevent the recurrence of a disease, disorder, or condition, or one or more symptoms associated with that disease, disorder, or condition. The preventive dose of a compound means the amount of the therapeutic agent, alone or in combination with other agents, that provides a preventive benefit in the prevention of the disease, disorder, or condition. The term “preventive dose” may include an amount that improves overall prevention or enhances the preventive efficacy of another preventive agent.

[0126] Detailed description of specific embodiments of the invention Compounds (e.g., compound of formula (I), compound of formula (V), or compound of formula (IX)), pharmaceutical compositions, and methods of use thereof for treating the diseases or disorders described herein. These are provided herein.

[0127] compound The compounds of the present invention, as described herein, are generally designed to modulate GABA function and thus act as neurostimulant steroids for the treatment and prevention of CNS-related conditions in subjects. Modulation, as used herein, refers to inhibition or synergy of GABA receptor function. Accordingly, the compounds and pharmaceutical compositions provided herein are found to have therapeutic uses for the prevention and / or treatment of CNS symptoms in mammals, including human and non-human mammals. Accordingly, as stated herein, the present invention includes, and extends to, the enumerated treatment methods, as well as compounds for such methods, and the use of such compounds for preparing pharmaceuticals useful for such methods.

[0128] In one aspect, what is provided herein is: Equation (I): [ka] A compound of or a pharmaceutically acceptable salt thereof, in formula (I), [ka] It represents a single or double bond, as far as the valence allows; R 2 , R 4 , R 6 , R 11a , and R 11b Each of these is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocykryl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1And here R A1 Each example is independently either a hydrogen atom, alkyl atom, alkenyl atom, alkynyl atom, carbocykyl atom, heterocyclyl atom, aryl atom, heteroaryl atom, 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, or two R atoms. A1 The groups bond to form a heterocyclic or heteroaryl ring; R A2 is alkyl, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, or heteroaryl; or R 11a and R 11b They come together to form an oxo; R 3 These are hydrogen, alkyl, alkenyl, alkynyl, carbocykrill, heterocyclyl, aryl, or heteroaryl; R 5 It either does not exist or is hydrogen; [ka] represents a single bond or a double bond, where at the site [ka] If one of them is a double bond, the other [ka] It is a single bond; [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 17 These are alkoxy, cyano, nitro, aryl, heteroaryl, or -C(O)R B1 -C(O)CH2R B1, or -C(O)CH2CH2R B1 And here R B1 is hydrogen, -OH, alkoxy, aryl, or heteroaryl; R 19 is hydrogen or alkyl; R 7 These include halogens, cyano, nitro, alkyl, alkenyl, alkynyl, carbocykryl, heterocyclyl, aryl, heteroaryl, and -OR. A1 , -SR A1 , -N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 It is a compound or a pharmaceutically acceptable salt thereof.

[0129] In some embodiments, R 3 It is an alkyl group.

[0130] In some embodiments, the compound of formula (I) is formula (Ia) or (Ib): [ka] It is a compound of [the compound].

[0131] In some embodiments, R 2 , R 4 , and R 6 , R 11a , and R 11b Each of them is independently a hydrogen atom.

[0132] In some embodiments, R 2 , R 4 , R 6 , R 11a , and R 11b These are all hydrogen. In some embodiments, R 2 , R 4 , and R 6Each of them is independently a halogen, a C1-C6 alkyl, a C1-C6 alkoxy, or -OH; in some embodiments, R 3 This is a C1-C6 alkyl group (for example, a C1-C6 haloalkyl group or -CH3 group).

[0133] In some embodiments, the compound of formula (I) is formula (II-a) or (II-b): [ka] It is a compound of [the compound].

[0134] In some embodiments, the compound of formula (I) is formula (II-c) or (II-d): [ka] It is a compound of R. In some embodiments, 19 is -CH3. In some embodiments, R 7 is alkyl (e.g., unsubstituted alkyl or -CH2OR) A1 ) or -OR A1 In some embodiments, R 7 is -CH3, -CH2CH3, -OH, -OCH3, or -CH2OCH3. In some embodiments, R 17 is -OCH3, -CN, or -C(O)CH3. In some embodiments, R 17 is -C(O)CH2R C1 In some embodiments, R 17 is -C(O)CH2R B1 In some embodiments, R 17 These are alkoxy, cyano, or -C(O)R B1 In some embodiments, R B1 is pyrazolyl (e.g., cyanosubstituted pyrazolyl). In some embodiments, R B1 is a tetrazolyl (e.g., a methyl-substituted tetrazolyl). In some embodiments, R B1 is a bicyclic heteroaryl (e.g., a methoxy-substituted bicyclic heteroaryl). In some embodiments, RB1 teeth, [ka] In some embodiments, R B1 teeth, [ka] That is the case.

[0135] In some embodiments, R 6 is a halogen. In some embodiments, R 6 It is fluorine.

[0136] In some embodiments, R 11a and R 11b Each of these is independently hydrogen, a C1-C6 alkyl (e.g., a C1-C6 haloalkyl), a C1-C6 alkoxy (e.g., a C1-C6 alkoxyhalo), or -OH. In some embodiments, R 11a and R 11b They come together to form an oxo. In some embodiments, R 17 R is a C1-C6 alkoxy (e.g., -OCH3), cyano, or nitro. In some embodiments, R 19 This refers to hydrogen or substituted or unsubstituted C1-C6 alkyl groups (e.g., -CH2OR X , here R X (These are hydrogen, C1-C6 alkyl, or C1-C6 alkoxy.)

[0137] In some embodiments, the compound of formula (I) is formula (III-a) or (III-b): [ka] A compound of formula (III-a) or (III-b), where Ra is hydrogen, a halogen, a C1-C6 alkyl (e.g., -CH3), or -OH. In some embodiments, the compound of formula (I) is of formula (IV-a) or (IV-b): [ka] A compound of, In equation (IV-a) or (IV-b), m is 0, 1, or 2; n is 0, 1, or 2; R b Each of them is independently hydrogen, a halogen, or a C1-C6 alkyl group; R c Each of these is independently a halogen, a C1-C6 alkyl (e.g., -CH3 or C1-C6 haloalkyl), a C1-C6 alkoxy, a cyano, or an -OH. In some embodiments, A is a 5-10 membered ring. In some embodiments, A is a condensed bicyclic ring. In some embodiments, A is a monocyclic heteroaryl or bicyclic heteroaryl.

[0138] In one phase, the following equation is provided: [ka] A compound or a pharmaceutically acceptable salt thereof In equation (V), [ka] It represents a single or double bond, as far as the valence allows; R 2 , R 4 , R 6 , R 11a , and R 11b Each of these is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocykryl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 And here R A1Each example is independently either a hydrogen atom, alkyl atom, alkenyl atom, alkynyl atom, carbocykyl atom, heterocyclyl atom, aryl atom, heteroaryl atom, 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, or two R atoms. A1 The groups bond to form a heterocyclic or heteroaryl ring; R A2 is alkyl, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, or heteroaryl; or R 11a and R 11b They come together to form an oxo; R 3 These are hydrogen, alkyl, alkenyl, alkynyl, carbocykrill, heterocyclyl, aryl, or heteroaryl; R 5 It either does not exist or is hydrogen; [ka] represents a single bond or a double bond, where at the site [ka] If one of them is a double bond, the other [ka] It is a single bond; [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 17 These are alkoxy, cyano, nitro, aryl, heteroaryl, -C(O)R B1 -C(O)CH2R B1 , or -C(O)CH2CH2R B1 And here RB1 is hydrogen, -OH, alkoxy, aryl, or heteroaryl; R 19 is hydrogen or alkyl; R 12 These include halogens, cyano, nitro, alkyl, alkenyl, alkynyl, carbocykryl, heterocyclyl, aryl, heteroaryl, and -OR. A1 , -SR A1 , -N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 It is a compound or a pharmaceutically acceptable salt thereof.

[0139] In some embodiments, R 3 It is alkyl.

[0140] In some embodiments, the compound of formula (V) is formula (Va) or (Vb): [ka] It is a compound of R. In some embodiments, 2 , R 4 , R 6 , R 11a , and R 11b Each of them is independently hydrogen. In some embodiments, R 2 , R 4 , R 6 , R 11a , and R 11b These are all hydrogen. In some embodiments, R 2 , R 4 , and R 6 Each of these is independently a halogen, a C1-C6 alkyl, a C1-C6 alkoxy, or -OH. In some embodiments, R 3 is a C1-C6 alkyl group (e.g., C1-C6 haloalkyl or -CH3). In some embodiments, the compound of formula (V) is formula (VI-a) or (VI-b): [ka] It is a compound of formula (V). In some embodiments, the compound of formula (V) is formula (VI-c) or (VI-d): [ka] It is a compound of R. In some embodiments, 19 is -CH3. In some embodiments, R 12 is -OR A1 In some embodiments, R 12 is -CH3, -CH2CH3, -OH, -OCH3, or -CH2OCH3. In some embodiments, R 17 is -OCH3, -CN, or -C(O)CH3. In some embodiments, R 17 is -C(O)CH2R C1 In some embodiments, R 17 is -C(O)CH2R B1 In some embodiments, R 17 These are alkoxy, cyano, or -C(O)R B1 That is the case.

[0141] In some embodiments, R B1 is pyrazolyl (e.g., cyanosubstituted pyrazolyl). In some embodiments, R B1 is a tetrazolyl (e.g., a methyl-substituted tetrazolyl). In some embodiments, R B1 is a bicyclic heteroaryl (e.g., a methoxy-substituted bicyclic heteroaryl). In some embodiments, R B1 teeth, [ka] In some embodiments, R B1 teeth, [ka] That is the case.

[0142] In some embodiments, R6 is a halogen. In some embodiments, R 6 It is fluorine.

[0143] In some embodiments, R 11a and R 11b Each of these is independently hydrogen, a C1-C6 alkyl (e.g., a C1-C6 haloalkyl), a C1-C6 alkoxy (e.g., a C1-C6 haloalkoxy), or -OH. In some embodiments, R 11a and R 11b They come together to form an oxo. In some embodiments, R 17 C1~C6 It is an alkoxy (e.g., -OCH3) or cyano. In some embodiments, R 19 This refers to hydrogen or substituted or unsubstituted C1-C6 alkyl groups (e.g., -CH2OR X , here R X (wherein is hydrogen, C1-C6 alkyl, or C1-C6 alkoxy). In some embodiments, the compound of formula (V) is formula (VII-a) or (VII-b): [ka] A compound of, In equation (VII-a) or (VII-b), R a is hydrogen, halogen, C1-C6 alkyl (e.g., -CH3), or -OH. In some embodiments, the compound of formula (V) is formula (VIII-a) or (VIII-b): [ka] A compound of, In equation (VIII-a) or (VIII-b), m is 0, 1, or 2, and n is 0, 1, or 2, R b Each of them is independently hydrogen, a halogen, or a C1-C6 alkyl; R cEach of these is independently a halogen, a C1-C6 alkyl (e.g., -CH3 or C1-C6 haloalkyl), a C1-C6 alkoxy, a cyano, or an -OH group.

[0144] In some embodiments, A is a 5- to 10-membered ring. In some embodiments, A is a fused bicyclic ring. In some embodiments, A is a monocyclic heteroaryl or bicyclic heteroaryl.

[0145] In one aspect, the formula (IX) provided herein is: [ka] A compound of or a pharmaceutically acceptable salt thereof, in formula (IX), [ka] It represents a single or double bond, as far as the valence allows; R 2 , R 4 , R 6 , R 11a , and R 11b Each of these is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocykryl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 And here R A1 Each example is independently either a hydrogen atom, alkyl atom, alkenyl atom, alkynyl atom, carbocykyl atom, heterocyclyl atom, aryl atom, heteroaryl atom, 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, or two R atoms. A1 The groups bond to form a heterocyclic or heteroaryl ring; R A2is alkyl, alkenyl, alkynyl, carbocykyl, heterocyclyl, aryl, or heteroaryl; or R 11a and R 11b They come together to form an oxo; R 3 These are hydrogen, alkyl, alkenyl, alkynyl, carbocykrill, heterocyclyl, aryl, or heteroaryl; R 5 It either does not exist or is hydrogen; [ka] represents a single bond or a double bond, where at the site [ka] If one of them is a double bond, the other [ka] It is a single bond; [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 17 These are alkoxy, cyano, nitro, aryl, heteroaryl, and -C(O)R B1 -C(O)CH2R B1 , or -C(O)CH2CH2R B1 And here R B1 is hydrogen, -OH, -N(R A1 )2, alkoxy, aryl, or heteroaryl; R 19 is hydrogen or alkyl; R 16These include halogens, cyano, nitro, alkyl, alkenyl, alkynyl, carbocykryl, heterocyclyl, aryl, heteroaryl, and -OR. A1 , -SR A1 , -N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 It is a compound or a pharmaceutically acceptable salt thereof.

[0146] In some embodiments, R 3 It is an alkyl group.

[0147] In some embodiments, the compound of formula (IX) is formula (IX-a) or (IX-b): [ka] It is a compound of [the compound].

[0148] In some embodiments, R 2 , R 4 , and R 6 , R 11a , and R 11b Each of them is independently hydrogen. In some embodiments, R 2 , R 4 , and R 6 , R 11a , and R 11b all are hydrogen. In some embodiments, R 2 , R 4 , and R 6 Each of these is independently a halogen, a C1-C6 alkyl, a C1-C6 alkoxy, or an -OH group.

[0149] In some embodiments, R 3 This is a C1-C6 alkyl group (for example, a C1-C6 haloalkyl group or -CH3 group).

[0150] In some embodiments, the compound of formula (IX) is formula (Xa) or (Xb): [ka] It is a compound of [the compound].

[0151] In some embodiments, the compound of formula (IX) is formula (Xc) or (Xd): [ka] It is a compound of [the compound].

[0152] In some embodiments, R 19 is -CH3. In some embodiments, R 16 is alkyl. In some embodiments, R 16 is -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2. In some embodiments, R 17 is -OCH3, -CN, or -C(O)CH3. In some embodiments, R 17 is -C(O)CH2R C1 In some embodiments, R 17 is -C(O)CH2R B1 In some embodiments, R 17 These are alkoxy, cyano, or -C(O)R B1 In some embodiments, R B1 is pyrazolyl (e.g., cyanosubstituted pyrazolyl). In some embodiments, R B1 is a tetrazolyl (e.g., a methyl-substituted tetrazolyl). In some embodiments, R B1 is a bicyclic heteroaryl (e.g., a methoxy-substituted bicyclic heteroaryl). In some embodiments, R B1 teeth, [ka] In some embodiments, R B1 teeth, [ka] That is the case.

[0153] In some embodiments, R 6 is a halogen. In some embodiments, R 6 It is fluorine.

[0154] In some embodiments, R 11a and R 11b Each of them independently consists of hydrogen, C1-C6 atoms. The group is a alkyl group (e.g., C1-C6 haloalkyl), a C1-C6 alkoxy group (e.g., C1-C6 haloalkoxy), or -OH group. In some embodiments, R 11a and R 11b They come together to form an oxo.

[0155] In some embodiments, R 17 The group is a C1-C6 alkoxy (e.g., -OCH3), cyano, or nitro group.

[0156] In some embodiments, R 19 This refers to hydrogen or substituted or unsubstituted C1-C6 alkyl groups (e.g., -CH2OR X , here R X (These are hydrogen, C1-C6 alkyl, and C1-C6 alkoxy.)

[0157] In some embodiments, the compound of formula (IX) is of formula (X- a1 ) or (X- b1 ): [ka] A compound of, Formula(X- a1 ) or (X- b1 ) in R a The group is hydrogen, a halogen, a C1-C6 alkyl group (e.g., -CH3), or an -OH group.

[0158] In some embodiments, the compound of formula (IX) is formula (XI-a) or (XI-b): [ka] A compound of, In equation (XI-a) or (XI-b), m is 0, 1, or 2, and n is 0, 1, or 2, R b Each of them is independently hydrogen, halogen, or C1-C6 alkyl, and R c Each of these is independently a halogen, a C1-C6 alkyl (e.g., -CH3 or C1-C6 haloalkyl), a C1-C6 alkoxy, a cyano, or an -OH group.

[0159] In some embodiments, A is a 5- to 10-membered ring. In some embodiments, A is a fused bicyclic ring. In some embodiments, A is a monocyclic heteroaryl or bicyclic heteroaryl.

[0160] The compounds listed in Table 1 below, or their pharmaceutically acceptable salts, are also provided herein. ru.

[0161] [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] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18] [Table 1-19]

[0162] Alternative Embodiments In alternative embodiments, the compounds described herein may also include one or more isotopic substitutions. For example, hydrogen may also 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, And so on. 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.

[0163] Pharmaceutical composition In one aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention (also referred to as the “active ingredient”) and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of the active ingredient.

[0164] 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.

[0165] 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.

[0166] 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.

[0167] The pharmaceutical compositions provided herein are also administered chronically ("chronic administration"). Chronic administration means the administration of a compound or its pharmaceutical composition over a long period of time, for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, or indefinitely, for example, over the remainder of the subject's life. In certain embodiments, chronic 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.

[0168] The pharmaceutical compositions of the present invention may be delivered using a variety of administration methods. For example, in certain embodiments, the pharmaceutical composition may be given as a bolus, for example, for the purpose of raising the concentration of the compound in the blood to an effective level. The placement of the bolus dose depends on the desired systemic level of the 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 a vein (e.g., by IV infusion) allow for faster delivery, which rapidly raises the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, for example by IV infusion, 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 infusion.

[0169] 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.

[0170] 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.

[0171] 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.

[0172] 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.

[0173] 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).

[0174] 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.

[0175] 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 miscible with a paraffinic ointment base or a water-miscible ointment base. Alternatively, the active ingredients may be formulated as a cream, for example, containing an oil-in-water cream base. Such transdermal formulations are well known in the art and generally contain further ingredients that enhance the skin penetration or stability of the active ingredient or formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.

[0176] 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.

[0177] 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).

[0178] 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.

[0179] 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.).

[0180] 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).

[0181] 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).

[0182] 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.

[0183] 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 1,4-linked glucose units, respectively, with one or more substituents optionally on the linked sugar moiety (including, but not limited to, substituted or unsubstituted methylation, hydroxyalkylation, acylation, and sulfoalkyl ether substitution). In certain embodiments, the cyclodextrin is sulfoalkyl ether β-cyclodextrin, for example, 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).

[0184] The injection 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 injection medium before use.

[0185] 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.

[0186] 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.

[0187] 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).

[0188] 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.

[0189] Instructions for use and handling In another context, a method is provided for reducing or preventing seizure activity in a subject, which comprises 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.

[0190] In some embodiments, such compounds are envisioned to be 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 impairment, 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). Exemplary CNS conditions associated with GABA regulation include sleep disorders [e.g., insomnia], mood disorders [e.g., depression, dysthymic disorder (e.g., mild depression), bipolar disorder (e.g., type I and / or type II)], and anxiety disorders [e.g., generalized anxiety disorder (GAD), social anxiety disorder]. (e.g., anxiety disorders), stress, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD)), schizophrenia spectrum disorder (e.g., schizophrenia, schizoaffective disorder), seizure disorders (e.g., epilepsy (e.g., status epilepticus (SE)), seizures), memory and / or cognitive impairment (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.

[0191] 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).

[0192] 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.

[0193] 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.

[0194] 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.

[0195] 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.

[0196] In another context, a method is provided for reducing or preventing PMS or PND 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.

[0197] 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.

[0198] 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.

[0199] Furthermore, in another scenario, by administering a therapeutically effective amount of the compound of the present invention to a subject... A method for treating attention disorders is provided. In a particular embodiment, this attention disorder is ADHD.

[0200] In certain embodiments, the compound is administered chronically to the subject. In certain embodiments, the compound is administered orally, subcutaneously, intramuscularly, or intravenously to the subject.

[0201] Neuroendocrine disorders and dysfunctions Methods that may be used to treat neuroendocrine disorders and dysfunctions are provided herein. Where used herein, “neuroendocrine disorder” or “neuroendocrine dysfunction” refers to a range of conditions caused by an imbalance 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, neuroendocrine disorders or dysfunctions are associated with women’s health disorders or conditions (e.g., women’s health disorders or conditions described herein). The associated neuroendocrine disorder or dysfunction is polycystic ovary syndrome (PCOS).

[0202] 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.

[0203] 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 that involve 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 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 siphonation, acute ataxia, tremor-paralysis or tardive dyskinesia induced by psychotropic agents, neuroleptic malignant syndrome, etc.) or drug-induced postural tremors); 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 (brainstem nerve calcification, corticobasal degeneration, multiple system atrophy, tremor palsy-ALS dementia complex, Parkinson's disease, post-encephalitis tremor palsy and progressive Examples include supranuclear palsy; disorders associated with muscle spasticity and spasticity or weakness (chorea (e.g., benign hereditary chorea, drug-induced chorea, unilateral ballism, Huntington's disease, neuroacanthocytosis, Sydenham's chorea and symptomatic chorea), dyskinesia (including tics such as compound tics, simple tics and symptomatic tics), myoclonus (including generalized myoclonus and focal cyloclonus), tremors (e.g., resting tremor, postural tremor and intention tremor) and This includes, but is not limited to, ataxia (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 injury (e.g., eye injury, retinopathy of the eye or macular degeneration); stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, neurotoxic disorders after perinatal asphyxia and cardiac arrest; Parkinson's disease; seizures; status epilepticus; stroke; tinnitus; tubular sclerosis; and neurodegeneration induced by viral infections (e.g., acquired immunodeficiency syndrome (AIDS) and brain injury). Neurodegenerative diseases also 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.

[0204] 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).

[0205] 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 a loss of interest or pleasure in activities that are normally enjoyable. Some people with clinical depression have difficulty sleeping, become thin, generally feel agitated, and become irritable. Clinical depression affects how an individual feels, thinks, and behaves and can lead to a range of emotional and physical problems. Individuals with clinical depression may struggle to perform daily activities and may feel that life is not worth living.

[0206] 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.

[0207] 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).

[0208] 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 developing PND. .

[0209] 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.

[0210] 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.

[0211] 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.

[0212] Catastrophic depression refers to major depressive disorder accompanied by motor and behavioral impairments and other symptoms. Individuals may become mute, enter a stuporous state, become immobile, or exhibit aimless or paranoid movements.

[0213] 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.

[0214] 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).

[0215] Bipolar disorder refers to a period of severe depression (mood disorder) that lasts for at least two years, interspersed with periods of major depression.

[0216] Depressive personality disorder (DPD) refers to a personality disorder characterized by depressive traits.

[0217] Recurrent brief depression (RBD) is a condition in which an individual experiences depressive episodes approximately once a month, each lasting for two weeks or less, typically less than two to three days.

[0218] Minor depressive disorder, or minor depression, refers to a type of depression in which at least two symptoms are present for two weeks.

[0219] 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.

[0220] Depression caused by a chronic condition refers to depression that is caused by a chronic medical condition such as cancer, chronic pain, chemotherapy, or chronic stress.

[0221] 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).

[0222] 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.

[0223] 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).

[0224] 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.

[0225] 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-injury, suicidal thoughts, and suicide attempts. The presence, severity, frequency, and duration of symptoms may vary from person to person. The symptoms of depression and their alleviation can be confirmed by a physician or psychologist (e.g., by a mental state assessment).

[0226] In some embodiments, the method provides a therapeutic effect (e.g., measured by a decrease in the Hamilton Depression Rating Scale (HAM-D)) within 4 days, 3 days, 2 days, 1 day; 96 hours, 84 hours, 72 hours, 60 hours, 48 ​​hours, 24 hours, 20 hours, 16 hours, 12 hours, 10 hours, 8 hours, or less). In some embodiments, the therapeutic effect is a decrease from baseline in the HAM-D score at the end of the treatment period (e.g., 12 hours, 24 hours, 48 ​​hours after administration; 24 hours, 48 ​​hours, 72 hours, 96 hours, or more). In some embodiments, the decrease from baseline in the HAM-D score ranges from severe (e.g., HAM-D score of 24 or higher) to asymptomatic (e.g., HAM-D score of 7 or lower). In some embodiments, the baseline score is approximately 10–52 (e.g., greater than 10, greater than 15, or greater than 20; 10–52, 12–52, 15–52, 17–52, 20–52, 22–52). In some embodiments, the baseline score is at least 10, 15, or 20. In some embodiments, the HAM-D score at the end of the treatment period is approximately 0–10 (e.g., less than 10; 0–10, 0–6, 0–4, 0–3, 0–2, 1.8). In some embodiments, the HAM-D score at the end of the treatment period is less than 10, less than 7, less than 5, or less than 3. In some embodiments, the reduction in HAM-D score is from a baseline score of approximately 20–30 (e.g., 22–28, 23–27, 24–27, 25–27, 26–27) to a HAM-D score of approximately 0–10 (e.g., less than 10; 0–10, 0–6, 0–4, 0–3, 0–2, 1.8). In some embodiments, the reduction in the HAM-D score at the end of the treatment period relative to the baseline HAM-D score is at least 1, 2, 3, 4, 5, 7, 10, 25, 40, 50, or 100 times (fold). In some embodiments, the percentage reduction in the baseline HAM-D score relative to the HAM-D score at the end of the treatment period is at least 50% (e.g., 60%, 70%, 80%, 90%). In some embodiments, the therapeutic effect is a reduction of at least 10, 15, or 20 points from baseline in the HAM-D score at the end of the treatment period (e.g., 12, 24, or 48 hours after administration; 24, 48, 72, or 96 hours or more). In some embodiments, the therapeutic effect is a reduction of at least 5, 7, or 10 points higher from baseline in the HAM-D score at the end of the treatment period (e.g., 12, 24, or 48 hours after administration; 24, 48, 72, or 96 hours or more) compared to the therapeutic effect obtained by placebo treatment.

[0227] In some embodiments, the method provides therapeutic effects (e.g., as measured by a decline in the Montgomery-Asberg Depression Rating Scale (MADRS)) within 4 days, 3 days, 2 days, 1 day; 96 hours, 84 hours, 72 hours, 60 hours, 48 ​​hours, 24 hours, 20 hours, 16 hours, 12 hours, 10 hours, 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 (related to outwardly expressed sadness, verbally expressed sadness, internal tension, decreased sleep, decreased appetite, difficulty concentrating, fatigue, inability to feel, pessimistic thinking, and suicidal thoughts). 0–6 indicates normal / no symptoms; 7–19 indicates mild depression; 20–34 indicates moderate depression; and over 34 indicates severe depression. In some embodiments, the therapeutic effect is a reduction from baseline in the MADRS score at the end of the treatment period (e.g., 12, 24, 48 hours after administration; 24, 48, 60, 72, 96 hours or more). In some embodiments, the reduction from baseline in the MADRS score ranges from severe (e.g., MADRS score greater than 30) to asymptomatic (e.g., MADRS score less than 20). For example, the mean change from baseline in the total MADRS score resulting from treatment with the compounds described herein is approximately -15, -20, -25, -30, while the mean change from baseline in the total MADRS score resulting from treatment with placebo is approximately -15, -10, -5.

[0228] 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.

[0229] In some embodiments, the method provides a therapeutic effect (e.g., measured by a decrease in the Clinical Global Impression Improvement Scale (CGI)) 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 a CGI score of 2 or less.

[0230] 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.

[0231] 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.

[0232] 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.

[0233] In panic disorder, individuals suffer from short bursts of intense fear and anxiety, often characterized by tremors, shaking, confusion, dizziness, nausea, and shortness of breath. These panic attacks (defined by APA as sudden fear or discomfort that peaks in less than 10 minutes) can last for several hours and can be triggered by stress, fear, or even exercise, although a specific cause is not always apparent. In addition to recurrent and unpredictable panic attacks, a diagnosis of phobic disorder also requires that the attacks have chronic consequences (either worry about the potential implications of the attack, persistent fear of future attacks, or significant behavioral changes related to the attack). Thus, individuals with phobic disorder experience symptoms even outside the scope of a particular panic episode. Often, unusual changes in heart rate are noticed by those suffering from panic, leading them to believe that their heart is somehow unwell or that they are about to experience another panic attack. In some cases, heightened perception of bodily functions (hypervigilance) occurs during panic attacks, in which case any perceived physiological changes are interpreted as a potentially life-threatening illness (i.e., excessive hypochondria).

[0234] 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.

[0235] 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).

[0236] 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.

[0237] 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).

[0238] 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.

[0239] 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.

[0240] 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).

[0241] Issues related to pregnancy include prenatal and prenatal care, pregnancy loss (miscarriage and stillbirth), premature birth and early delivery, sudden infant death syndrome (SIDS), breastfeeding, and birth defects.

[0242] A miscarriage refers to the spontaneous termination of a pregnancy within 20 weeks of gestation.

[0243] Abortion refers to the intentional termination of a pregnancy, which can be performed up to 28 weeks of gestation.

[0244] Infertility and related disorders include uterine fibrosis, polycystic ovary syndrome, endometriosis, and primary ovarian dysfunction.

[0245] 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.

[0246] Other disorders and conditions that affect only women include Turner syndrome, Rett syndrome, and ovarian and cervical cancer.

[0247] 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.

[0248] Menopause refers to the 12 months after 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 mood swings, can disrupt sleep, reduce energy, or cause anxiety or sadness. It can cause feelings of loss. Menopause includes spontaneous menopause and surgical menopause (induced menopause resulting from 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.

[0249] epilepsy Compounds of formula (I), compounds of formula (V), or compounds of formula (IX), or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable compositions thereof may be used to treat, for example, disorders described herein, such as epilepsy, status epilepticus, or seizures, as described herein, for example, as described in WO2013 / 112605 and WO / 2014 / 031792, whose entire contents are incorporated herein.

[0250] 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.

[0251] 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).

[0252] Status epilepticus (SE) Status epilepticus (SE) can include, for example, convulsive status epilepticus, such as early status epilepticus, established status epilepticus, refractory status epilepticus, and extremely refractory status epilepticus; non-convulsive status epilepticus, such as generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptic discharges; and periodic unilateral epileptic discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epilepticus seizures and can include early status epilepticus, established status epilepticus, refractory status epilepticus, and extremely refractory status epilepticus. Early status epilepticus is treated with first-line therapy. Established status epilepticus is characterized by persistent status epilepticus despite first-line treatment, and second-line treatment is initiated. Refractory status epilepticus is characterized by persistent status epilepticus despite first-line and second-line treatment, and general anesthetics are generally administered. Extremely refractory status epilepticus is characterized by persistent status epilepticus despite first-line treatment, second-line treatment, and 24 hours or more of general anesthetic treatment.

[0253] 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.

[0254] Compounds of formula (I), compounds of formula (V), or compounds of formula (IX), or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable compositions thereof, also predates CNS disorders, such as traumatic brain injury, status epilepticus, or convulsive epileptic seizures. It can be administered prophylactically to subjects with status epilepticus, such as early status epilepticus, established status epilepticus, refractory status epilepticus, and extremely refractory status epilepticus; non-convulsive status epilepticus, such as generalized status epilepticus and complicated partial status epilepticus; generalized periodic epileptic discharges; and periodic unilateral epileptic discharges.

[0255] 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.

[0256] 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.

[0257] 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.

[0258] 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.

[0259] Absence seizures cause brief (only a few seconds) periods of loss of consciousness with little or no symptoms. Patients (most frequently children) typically stop their activities and stare blankly. These seizures begin and end suddenly and can occur several times a day. Patients are usually unaware they are having seizures unless they notice they are "losing time."

[0260] 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.

[0261] Clonic seizures are recurrent, rhythmic spasms that involve both sides of the body simultaneously.

[0262] Tonic seizures are characterized by muscle rigidity.

[0263] 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.

[0264] The seizures described herein 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; myoclonus 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 Seizures may include: laughter seizures; generalized seizures; infantile spasms; Jacksonian seizures; generalized bilateral myoclonic seizures; multifocal seizures; neonatal seizures; nocturnal seizures; occipital lobe seizures; post-traumatic seizures; microseizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures. In some embodiments, seizures are generalized seizures associated with Dravet syndrome, Lennox-Gastaut syndrome, compound tuberous sclerosis, Rett syndrome, or PCDH19 girl epilepsy.

[0265] 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.

[0266] 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 disorders, liver diseases, 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 can be classified into physiological tremors, fatigue-induced physiological tremors (enhanced physiologic tremors), essential tremor syndromes (including classical essential tremor, primary orthostatic tremor, and task-specific and positional tremors), dystonic tremors, Parkinsonian tremors, cerebellar tremors, Holmes tremor (i.e., red nucleus tremor), palatal tremors, neuropathic tremors, toxic or drug-induced tremors, and psychogenic tremors.

[0267] 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).

[0268] 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).

[0269] 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.

[0270] Essential tremor, or benign essential tremor, is the most common type of tremor. Essential tremor can be mild and non-progressive in some cases, starting on one side of the body but becoming bilateral within three years. The tremors can be slow-progressing and affect only certain parts of the body. While the hands are most frequently affected, the head, voice, tongue, legs, and trunk may 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.

[0271] 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.

[0272] 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.

[0273] 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.

[0274] 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.

[0275] 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.

[0276] 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.

[0277] 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.

[0278] Chorea is a neurological disorder typically characterized by rhythmic, involuntary movements affecting the shoulders, hips, and face.

[0279] Huntington's disease is a genetic disorder that weakens nerve cells in the brain. Symptoms include uncontrolled movement, clumsiness, and balance problems. Huntington's disease can interfere with walking, speaking, and swallowing.

[0280] Ataxia refers to the loss of complete control over bodily movements and can affect fingers, hands, arms, legs, body, speech, and eye movements.

[0281] Myoclonus and startle are responses to sudden and unexpected stimuli that may be auditory, tactile, visual, or vestibular.

[0282] 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.

[0283] Lower limb restlessness syndrome is a neurological sensorimotor disorder characterized by an irresistible urge to move the legs while at rest.

[0284] 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.

[0285] 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.

[0286] 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 a combination of 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, paralyzing agents, analgesics) to achieve a very specific combination of results. Anesthesia allows patients to undergo surgical and other procedures without experiencing the difficulties and pain they would otherwise experience.

[0287] Sedation is generally the reduction of nervousness or agitation through the administration of pharmacological agents to facilitate medical or diagnostic procedures.

[0288] Sedation and analgesia encompass a continuum of states of consciousness ranging from minimal sedation (anxiety relief) to general anesthesia.

[0289] 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.

[0290] 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.

[0291] 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.

[0292] 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.

[0293] 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).

[0294] 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.

[0295] 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]

[0296] For the purpose of enabling a better understanding of the present invention as described herein, the following examples are provided. The examples of synthesis described herein are provided to illustrate the present invention as provided herein and should not be construed as limiting its scope.

[0297] 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.

[0298] 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.

[0299] 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.

[0300] Exemplary general method for preparative HPLC: Column: Durashell. Mobile phase: A: Water, B: Acetonitrile. %B at 0 min: 41%, %B at 8 min: 71%, flow rate: 35 mL / min, detection wavelength: 220 nm.

[0301] Exemplary general method for analytical HPLC: Mobile phase: A: Water (10 mM NH4HCO3), B: Acetonitrile, Gradient: 5% to 95% of B for 1.6 or 2 minutes; Flow rate: 1.8 or 2 mL / min; Column: XBridge C18, 4.6 × 50 mm, 3.5 □ m, 45°C

[0302] Exemplary general method for SFC: Column: CHIRALPAK® AD (250 mm × 30 mm, 5 μm), A = supercritical CO2, B = MeOH (0.1% NH3-H2O), A:B = 70:30, flow rate: 60 mL / min, column temperature: 38 °C, nozzle pressure: 100 bar, detection wavelength: 220 nm.

[0303] Examples of LCMS conditions include the following: [Table A] [Table B] [Table C]

[0304] TBPS-binding steroid inhibition Using rat cortical membranes in the presence of 5 mM GABA [ 35 A binding assay for S]-t-butylbicyclophosphorothionate (TBPS) 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).

[0305] 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 [ 35Incubate 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. Measure the radioactivity bound to the filter by liquid scintillation spectrometry. Perform nonlinear curve fitting of the entire dataset for each drug, averaged for each concentration, using Prism (GraphPad). If the sum of squares is significantly lower by the F-test, fit the data to a partial inhibition model instead of a complete inhibition model. Similarly, if the sum of squares is significantly lower by the F-test, fit the data to a two-component inhibition model instead of a one-component inhibition model. Apply the data to this. The concentration of the test compound that causes 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.

[0306] Various compounds in vitro 35 Screening may be performed or may be performed to measure the potential of [S]-TBPS binding regulators. These assays are performed or may be performed according to the procedures discussed above. The results of the TBPS binding assays are shown in Table 2.

[0307] Abbreviation PCC: Pyridinium chlorochromate; t-BuOK: Potassium tert-butoxide; 9-BBN: 9-borabicyclo[3.3.1]nonane; Pd(t-Bu3P)2: Bis(tri-tert-butylphosphine)palladium(0); AcCl: Acetyl chloride; i-PrMgCl: Isopropyl magnesium chloride; TBSCl: Tert-butyl(chloro)dimethylsilane; (i-PrO)4Ti: Titanium tetraisopropoxide; BHT: 2,6-di-t-butyl-4-methylphenoxide; Me: Methyl; i-Pr :Isopropyl; t-Bu:tert-butyl; Ph:Phenyl; Et:Ethyl; Bz:Benzoyl; BzCl:Benzoyl chloride; CsF:Cesium fluoride; DCC:Dicyclohexylcarbodiimide; DCM:Dichloromethane; DMAP:4-Dimethylaminopyridine; DMP:Des-Martin-Periodinane; EtMgBr:Ethylmagnesium bromide; Â:Ethyl acetate; TEA:Triethylamine; AlaOH:Alanine; Boc:t-Butoxycarbonyl; Py:Pyridine; TBAF:Tetra-fluoride n-butylammonium; THF: tetrahydrofuran; TBS: t-butyldimethylsilyl; TMS: trimethylsilyl; TMSCF3: (trifluoromethyl)trimethylsilane; Ts: p-toluenesulfonyl; Bu: butyl; Ti(OiPr)4: tetraisopropoxytitanium; LAH: lithium aluminum hydride; LDA: lithium diisopropylamide; LiOH.H2O: lithium hydroxide hydrate; MAD: methylaluminum bis(2,6-di-t-butyl-4-methylphenoxide); MeCN: acetonyl Toryl; NBS: N-bromosuccinimide; Na2SO4: sodium sulfate; Na2S2O3: sodium thiosulfate; PE: petroleum ether; MeCN: acetonitrile; MeOH: methanol; Boc: t-butoxycarbonyl; MTBE: methyl tert-butyl ether; EDCI: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate.

[0308] Abbreviation PCC: Pyridinium chlorochromate; t-BuOK: Potassium tert-butoxide; 9-BBN: 9-Borabicyclo[3.3.1]nonane; Pd(t-Bu3P)2: Bis(tri-tert-butylphosphine)palladium(0); AcCl: Acetyl chloride; i-PrMgCl: Isopropyl magnesium chloride; TBSCl: Tert-butyl(chloro)dimethylsilane; (i-PrO)4Ti: Titanium tetraisopropoxide; BHT: 2,6-di-t-butyl-4-methylphenoxide; Me: Methyl; i-Pr: Iso- Propyl; t-Bu: tert-butyl; Ph: phenyl; Et: ethyl; Bz: benzoyl; BzCl: benzoyl chloride; CsF: cesium fluoride; DCC: dicyclohexylcarbodiimide; DCM: dichloromethane; DMAP: 4-dimethylaminopyridine; DMP: des-martin-periodinane; EtMgBr: ethylmagnesium bromide; Â: ethyl acetate; TEA: triethylamine; AlaOH: alanine; Boc: t-butoxycarbonyl; Py: pyridine; TBAF: tetra-n-butylammonium fluoride Nium; THF: Tetrahydrofuran; TBS: t-Butyldimethylsilyl; TMS: Trimethylsilyl; TMSCF3: (Trifluoromethyl)trimethylsilane; Ts: p-Toluenesulfonyl; Bu: Butyl; Ti(OiPr)4: Tetraisopropoxytitanium; LAH: Lithium aluminum hydride; LDA: Lithium diisopropylamide; LiOH.H2O: Lithium hydroxide hydrate; MAD: Methylaluminum bis(2,6-di-t-butyl-4-methylphenoxide); MeCN: Acetonitrile; NBS: N-bromosuccinimide; Na2SO4: sodium sulfate; Na2S2O3: sodium thiosulfate; PE: petroleum ether; MeCN: acetonitrile; MeOH: methanol; Boc: t-butoxycarbonyl; MTBE: methyl tert-butyl ether; EDCI: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate.

[0309] Example 1. Synthesis of Compounds 1 and 2 [ka]

[0310] Step 1. To a solution of A1 (100g, 290 mmol) in THF (500mL), Pd-C (wet, 10%, 10g) was added under N2 conditions. This suspension was degassed under reduced pressure (under vacuum) and purged with H2 three times. This mixture was then subjected to H2 (15psi) conditions. The mixture was stirred at 25°C for 48 hours to obtain a black suspension. The reaction mixture was filtered through a Celite pad and washed with THF (500 mL). The filtrate was concentrated to obtain A2 (98 g, 97%) as a solid.

[0311] 1 H NMR (400MHz, CDCl3) δ 4.73-4.62 (m, 1H), 2.65-2.54 (m, 1H), 2.51-2.32 (m, 3H), 2.20-2.06 (m, 2H), 2.04 (s, 3H), 1.95-1.86 (m, 1H), 1.84-1.67 (m, 5H), 1.67-1.42 (m, 5H), 1.25-1.02 (m, 6H), 0.91-0.81 (m, 3H).

[0312] Step 2. To a solution of MePPh3Br (20.6 g, 57.7 mmol, 1.0 equivalent) in THF (200 mL), t-BuOK (6.47 g, 57.7 mmol, 1.0 equivalent) was added at 0°C. After addition, this reaction mixture was heated to 20°C and stirred for 1 hour. Next, this mixture was added to a solution of A2 (20 g, 57.7 mmol, 1.0 equivalent) in THF (200 mL), and this reaction mixture was stirred at 20°C for 2 hours. This mixture was treated with NH4Cl (100 mL, 10%) and extracted with SiO2 (2 × 100 mL). The organic phase was separated and concentrated under reduced pressure to obtain the product as a crude residue. This residue was converted to MeOH / H2O( Crude residue was obtained by grinding 400 ml (1 / 1) at 20°C. This crude residue was dissolved in DCM (200 mL), washed with saturated brine (2 × 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain A3 (19 g, 96%) as a solid.

[0313] 1 H NMR (400MHz, CDCl3) δ 4.75 (s, 1H), 4.64 (s, 1H), 2.51-2.44 (m, 1H), 2.35-2.32 (m, 1H), 2.23-2.11 (m, 2H), 2.04 (s, 3H), 1.99-1.93 (m, 1H), 1.86-1.63 (m, 7H), 1.54-1.19 (m, 7H), 1.08-1.01 (m, 1H), 0.99 (s, 3H), 0.90 (s, 3H), 0.89-0.81 (m, 1H).

[0314] Step 3. To a solution of A3 (19 g, 55.1 mmol) in ethanol (100 mL), Pd-C (dried, 10%, 2 g) was added under N2 conditions. This suspension was degassed under reduced pressure and purged with H2 three times. The mixture was stirred under H2 at 15°C for 20 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain A4 (18 g, 95%) as a solid.

[0315] 1 H NMR (400MHz, CDCl3) δ 4.72-4.67 (m, 1H), 2.46-2.40 (m, 1H), 2.13-2.03 (m, 4H), 1.94-1.91 (m, 1H), 1.80-1.22 (m, 15H), 1.15-1.01 (m, 4H), 0.94-0.75 (m, 8H).

[0316] Step 4. To a solution of A4 (18 g, 51.9 mmol) in MeOH (200 mL), K2CO3 (28.6 g, 207 mmol) was added all at once at 15 °C under N2 conditions. This mixture was stirred at 15 °C for 2 hours and quenched with water (100 mL). The aqueous phase was extracted with DCM (3 × 100 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain A5 (15.2 g, 96%) as a colorless oil.

[0317] 1 H NMR (400MHz, CDCl3) δ 3.62-3.60 (m, 1H), 2.62-2.40 (m, 1H), 2.11-2.04 (m, 2H), 1.96-1.90 (m, 1H), 1.80-1.02 (m, 20H), 0.90-0.80 (m, 6H), 0.76-0.70 (m, 1H).

[0318] Step 5. To a solution of A5 (8 g, 26.2 mmol) in DCM (100 mL), silica gel (11.2 g) and PCC (11.2 g, 52.6 mmol) were added at 25°C. The reaction mixture was stirred at 25°C for 1 hour. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. To a solution of this crude product in DCM (20 mL), silica gel (20 g) and PE (100 mL) were added. After stirring at 25°C for 30 minutes, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain A6 (7 g) as a solid.

[0319] 1 H NMR (400MHz, CDCl3) δ 2.42-2.06 (m, 8H), 1.80-1.77 (m, 4H), 1.45-1.22 (m, 8H), 1.05-0.84 (m, 10H).

[0320] Step 6. The suspension of LiCl (2.05 g, 48.5 mmol, anhydrous) in THF (200 mL, anhydrous) was stirred at 10°C under N2 for 30 minutes. FeCl3 (4.11 g, 25.4 mmol, anhydrous) was added at 10°C. After cooling to -30°C, MeMgBr (30.8 mL, 3 M in diethyl ether) was added dropwise at -30°C. After stirring at -30°C for 10 minutes, A6 (7 g, 23.1 mmol) was added at -30°C. This mixture was stirred at -15°C for 2 hours and quenched with citric acid (200 mL, 10% aqueous solution). This mixture was extracted with ELISA (2 × 100 mL). The combined organic phases were washed with saturated brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This was then purified by silica gel column (PE / SiO=0~10 / 1) to obtain A7 (1 g, 14%, Rf=0.45 (in PE / SiO)) and A8 (0.8 g, 11%, Rf=0.40 (in PE / SiO) and a mixture (4 g) were obtained as solids. A7:

[0321] 1 H NMR (400MHz, CDCl3) δ 2.48-2.41 (m, 1H), 2.13-2.08 (m, 1H), 1.97-1.90 (m, 1H), 1.84-1.67 (m, 4H), 1.55-1.47 (m, 5H), 1.41-1.25 (m, 5H), 1.23-1.01 (m, 8H), 0.97-0.94 (m, 3H), 0.86 (s, 3H), 0.79 (s, 3H).

[0322] The stereochemistry of A7 at C7 was confirmed by NOE.

[0323] A8: 1H NMR (400MHz, CDCl3) δ 2.48-2.38 (m, 1H), 2.12-2.07 (m, 1H), 1.79-1.73 (m, 2H), 1.56-1.49 (m, 4H), 1.46-1.38 (m, 2H), 1.32-1.19 (m, 12H), 1.03-0.97 (m, 4H), 0.87 (s, 3H), 0.86-0.76 (m, 2H), 0.73 (s, 3H).

[0324] The stereochemistry of A8 at C7 was confirmed by NOE.

[0325] Step 7a (Compound 1). t-BuOH (2 mL) and t-BuOK (703 mg, 6.27 mmol) were added to a super-dried bottom. After evaporation and packing with N2, a solution of A7 (200 mg, 0.627 mmol) in DME (1 mL) was added. After 30 minutes, a solution of TosMic (243 mg, 1.25 mmol) in DME (1 mL) was added. The mixture turned yellow. The resulting mixture was stirred at 25°C for 16 hours and quenched with water. This mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine. The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography using (petroleum ether / ethyl acetate = 10 / 1) to obtain Compound 1 (50 mg, 24%) as a solid.

[0326] 1 H NMR (400MHz, CDCl3) δ2.30-2.24 (m, 1H), 2.16-2.06 (m, 1H), 1.97-1.87 (m, 2H), 1.83-1.71 (m, 3H), 1.67-1.58 (m, 1H), 1.54-1.42 (m, 5H), 1.39-1.24 (m, 4H), 1.20-1.01 (m, 9H), 0.93-0.88 (m, 6H), 0.77 (s, 3H).

[0327] LCMS Rt = 1.918 min (3.0 min chromatography), 10⁻⁸ AB₃ MIN E.M, purity 100%, C 22 H 34 N[M+H-H2O] + MS ESI calculated value: 312, measured value: 312.

[0328] Step 7b (Compound 2). t-BuOH (2 mL) and t-BuOK (703 mg, 6.27 mmol) were added to a round-bottom flask dried in an oven. The reactor was evaporated and packed with N2. A8 (200 mg, 0.627 mmol) in DME (1 mL) was added to the suspension. After 30 minutes, TosMIC (243 mg, 1.25 mmol) in DME (1 mL) was added. The mixture turned yellow. The resulting mixture was stirred at 25°C for 16 hours. Water was added and the mixture was stirred. This was then extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine. The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography using elution with petroleum ether:ethyl acetate (4:1) to obtain Compound 2 (13 mg, 6%) as a solid.

[0329] 1 H NMR (400MHz, CDCl3) δ 2.26-2.17 (m, 1H), 2.14-2.00 (m, 1H), 1.99-1.85 (m, 3H), 1.73-1.67 (m, 1H), 1.56-1.44 (m, 5H), 1.30-1.24 (m, 4H), 1.20 (s, 3H), 1.17-1.09 (m, 4H), 1.04-0.88 (m, 8H), 0.85-0.76 (m, 2H), 0.72 (s, 3H).

[0330] LCMS Rt=1.939 min (3.0 min chromatography), 10⁻⁸ AB₃ MIN E.M, purity 100%, C 22 H 34 NO[M+H-H2O] + MS ESI calculated value: 312, measured value: 312.

[0331] Example 2. Synthesis of compounds 3 and 4. [ka]

[0332] Step 1a (B1). NaBH4 (47.2 mg, 1.25 mmol) was added at 25°C to a solution of A7 (200 mg, 0.627 mmol) in MeOH (5 mL). After stirring at 25°C for 30 minutes, the reaction product was quenched by adding water (10 mL) and extracted with DCM (2 × 20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain B1 (180 mg, crude) as a solid, which was used directly for the next step without further purification.

[0333] 1 H NMR (400MHz, CDCl3) δ 3.67-3.62 (m, 1H), 2.11-2.02 (m, 1H), 1.82-1.75 (m, 3H), 1.63-1.37 (m, 11H), 1.34-1.20 (m, 8H),1.14-1.01(m, 4H), 0.90 (d, J = 4.0 Hz, 2H), 0.78 (s, 3H), 0.74 (s, 3H).

[0334] Step 2a (Compound 3). To a solution of B1 (180 mg, 0.561 mmol) in THF (5 mL), KOH (94.2 mg, 1.68 mmol) and Me2SO4 (0.282 mg, 0.211 mL, 2.24 mmol) were added at 0°C. The mixture was then heated to 25°C and stirred at the same temperature for 16 hours. The mixture was quenched with 50 mL of water and extracted with Depositphotos (2 × 30 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column (PE / Depositphotos = 0~10 / 1) to obtain Compound 3 (21 mg, 11%) as a solid.

[0335] 1H NMR (400MHz, CDCl3) δ 3.34 (s, 3H), 3.22 (t, J = 8.0 Hz, 1H), 2.04-1.96 (m, 1H), 1.88-1.71 (m, 3H), 1.63-1.56 (m, 2H), 1.54-1.34 (m, 7H), 1.32-1.17 (m, 8H), 1.16-0.97 (m, 5H), 0.90 (d, J = 4.0 Hz, 2H), 0.76 (s, 3H), 0.74 (s, 3H).

[0336] LCMS Rt=2.050 min (3.0 min chromatography), 10⁻⁸ AB₃ MIN E.M, purity 100%, C 22 H 37 O[M+H-H2O] + The MS ESI calculated value is 317, and the measured value is also 317.

[0337] Step 1b (B2). NaBH4 (47.2 mg, 1.25 mmol) was added at 25°C to a solution of A8 (200 mg, 0.627 mmol) in MeOH (5 mL). After stirring at 25°C for 30 minutes, the reaction product was quenched by adding water (10 mL) and extracted with DCM (2 × 20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain B2 (170 mg, crude) as a solid, which was used directly for the next step without further purification.

[0338] 1 H NMR (400MHz, CDCl3) δ 3.62-3.56 (m,1H), 2.08-1.99 (m,1H), 1.81-1.76 (m, 2H), 1.68-1.62 (m, 1H), 1.58-1.38 (m, 7H), 1.33-0.99 (m, 15H), 0.94 (d, J=8.0 Hz, 2H), 0.84-0.77 (m, 1H), 0.75 (s, 3H), 0.73 (s, 3H).

[0339] Step 2b (Compound 4). To a solution of B2 (170 mg, 0.530 mmol) in THF (5 mL), KOH (88.6 mg, 1.58 mmol) and Me2SO4 (0.266 mg, 0.2 mL, 2.11 mmol) were added at 0°C. The mixture was then heated to 25°C and stirred at the same temperature for 16 hours. The mixture was quenched by adding 50 mL of water and extracted with siRNA (2 × 30 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column (PE / siRNA = 0~10 / 1) to obtain compound 4 (21 mg, 11%) as a solid. 1 H NMR (400MHz, CDCl3) δ 3.34 (s, 3H), 3.16 (t, J = 8.0 Hz, 1H), 2.02-1.93 (m, 1H), 1.88 (dt, J = 4.0, 12.0 Hz, 1H), 1.77-1.74 (m, 1H), 1.64-1.39 (m, 9H), 1.33-1.08 (m, 12H), 1.03-0.96 (m, 1H), 0.93 (d, J = 8.0 Hz, 2H), 0.80-0.74 (m, 1H), 0.75 (s, 3H), 0.71 (s, 3H).

[0340] LCMS Rt=2.079 min (3.0 min chromatography), 10⁻⁸ AB₃ MIN E.M, purity 100%, C 22 H 37 O[M+H-H2O] + The MS ESI calculated value is 317, and the measured value is also 317.

[0341] Example 3. Synthesis of compounds 5 and 6. [ka]

[0342] Step 1. To a suspension of PPh3EtBr (1.91 g, 5.15 mmol) in THF (10 mL), t-BuOK (0.577 g, 5.15 mmol) was added at 10 °C. The suspension turned dark red. After stirring at 40 °C for 30 minutes, a solution of A7 (0.55 g, 1.72 mmol) in THF (2 mL) was added at 40 °C. After stirring at 40 °C for 1 hour, the reaction mixture was poured onto 20 g of crushed ice and stirred for 15 minutes. The organic layer was separated, and the aqueous phase was extracted with SiO2 (2 × 20 mL). The combined organic phases were washed with saturated brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by flash column (PE with 0-10% SiO2) to obtain C1 (350 mg, 62%) as a solid.

[0343] 1 H NMR (400MHz, CDCl3) δ 5.14-5.08 (m, 1H), 2.41-2.32 (m, 1H), 2.26-2.12 (m, 2H), 1.87-1.70 (m, 2H), 1.67-1.44 (m, 10H), 1.40-1.08 (m, 11H), 1.07-1.03 (m, 1H), 1.05-0.99 (m, 1H), 0.91 (d, J = 6.8 Hz, 3H), 0.86 (s, 3H), 0.77 (s, 3H).

[0344] Step 2. To a solution of C1 (200 mg, 0.605 mmol) in THF (3 mL), a solution of BH3-Me2S (0.605 mL, 6.05 mmol) was added dropwise at 0°C. This solution was stirred at 15°C for 3 hours. After cooling to 0°C, a solution of NaOH (3.62 mL, 2 M) was added very slowly. After addition, H2O2 (683 mg, 6.05 mL) was added. 30% of ol (in water) was slowly added, and the internal temperature was maintained below 10°C. After stirring at 15°C for 2 hours, saturated Na2S2O3 aqueous solution (50 mL) was added until the reaction solution became clear. This mixture was extracted with SiO2 (3 × 50 mL). The combined organic solution was washed with saturated Na2S2O3 aqueous solution (2 × 20 mL) and brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain a crude product (180 mg) as a solid, which was used in the next step without further purification.

[0345] 1 H NMR (400MHz, CDCl3) δ 3.77-3.66 (m, 1H), 1.82-1.71 (m, 3H), 1.54-1.42 (m, 8H), 1.32-1.06 (m, 19H), 0.91 (d, J = 8.0 Hz, 3H), 0.75 (s, 3H), 0.65 (s, 3H).

[0346] Step 3. To a solution of C3 (180 mg, 0.516 mmol) in DCM (5 mL), silica gel (222 mg) and PCC (222 mg, 1.03 mmol) were added at 25°C. The reaction mixture was stirred at 25°C for 1 hour. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. To a solution of the crude product in DCM (20 mL), silica gel (20 g) and PE (100 mL) were added. This mixture was stirred at 25°C for 30 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by flash column (0-10% ethyl acetate in PE) to obtain compound 5 (29 mg, 16%) as a solid.

[0347] 1 H NMR (400 MHz, CDCl3) δ 2.53 (t, J = 8.0 Hz, 1H), 2.20-2.14 (m, 1H), 2.11(s, 3H), 2.01-1.94 (m, 1H), 1.83-1.73 (m, 2H), 1.70-1.59 (m, 3H), 1.55-1.43 (m, 5H), 1.39-1.12 (m, 12H), 1.04-1.01 (m, 1H), 0.92 (d, J = 8.0 Hz, 3H), 0.76 (s, 3H), 0.60 (s, 3H).

[0348] LCMS Rt=2.150 min (3.0 min chromatography), 10⁻⁸ AB₃ MIN E.M, purity 100%, C 23 H 37 O[M+H-H2O] + The MS ESI calculated value is 329, and the measured value is also 329.

[0349] Step 4. To a suspension of PPh3EtBr (1.21 g, 3.27 mmol) in THF (10 mL), t-BuOK (0.366 g, 3.27 mmol) was added at 10 °C. The suspension turned dark red. After stirring at 40 °C for 30 minutes, a solution of A8 (0.35 g, 1.09 mmol) in THF (2 mL) was added at 40 °C, and the reaction mixture was stirred at 40 °C for 1 hour. This reaction mixture was poured onto 20 g of crushed ice and stirred for 15 minutes. The organic layer was separated, and the aqueous phase was extracted with ELISA (2 × 20 mL). The combined organic phases were washed with saturated brine (2 × 20 mL), dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by flash column (0-10% ELISA in PE) to obtain C3 (140 mg, 39%) as a solid.

[0350] 1 H NMR (400 MHz, CDCl3) δ 5.15-5.12 (m, 1H), 2.31-2.22 (m, 3H), 1.81-1.73 (m, 1H), 1.70-1.61 (m, 4H), 1.56-1.40 (m, 7H), 1.34-1.18 (m, 12H), 0.95 (d, J=4.0 Hz, 3H), 0.89 (s, 3H), 0.87-0.79 (m, 1H), 0.72 (s, 3H).

[0351] Step 5. To a solution of C3 (120 mg, 0.363 mmol) in THF (3 mL), a solution of BH3-Me2S (0.363 mL, 3.63 mmol) was added dropwise at 0°C. This solution was stirred at 15°C for 3 hours. After cooling to 0°C, a solution of NaOH (2.17 mL, 2 M) was added very slowly. After the addition, H2O2 (410 mg, 3.63 mmol, 30% in water) was slowly added, maintaining the internal temperature below 10°C. The resulting solution was stirred at 15°C for 2 hours. Then, a saturated aqueous solution of Na2S2O3 (50 mL) was added until the reaction solution became clear. This mixture was extracted with ELISA (3 × 50 mL). The combined organic solution was washed with saturated Na2S2O3 aqueous solution (2 × 20 mL) and brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain a crude product (100 mg) as a solid, which was used in the next step without further purification.

[0352] 1 H NMR (400MHz, CDCl3) δ 3.76-3.64 (m, 1H), 1.86-1.79 (m, 3H), 1.54-1.39 (m, 8H), 1.28-1.17 (m, 17H), 0.95 (d, J = 6.0 Hz, 3H), 0.82-0.74 (m, 2H), 0.71 (s, 3H), 0.67 (s, 3H).

[0353] Step 6. To a solution of C4 (100 mg, 0.286 mmol) in DCM (5 mL), silica gel (123 mg) and PCC (123 mg, 0.572 mmol) were added at 25°C. The reaction mixture was stirred at 25°C for 1 hour. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. To a solution of the crude product in DCM (20 mL), silica gel (20 g) and PE (100 mL) were added. This mixture was stirred at 25°C for 30 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. This crude product was purified by flash column (0-10% ethyl acetate in PE) to obtain compound 6 (13 mg, 13%) as a solid. 1H NMR (400MHz, CDCl3) δ 2.48 (t, J = 9.2 Hz, 1H), 2.16-2.09 (m, 4H), 2.01-1.95 (m, 1H), 1.86-1.82 (m, 1H), 1.73-1.59 (m, 2H), 1.54-1.42 (m, 5H), 1.40-1.14 (m, 13H), 1.05-0.96 (m, 1H), 0.95 (d, J = 6.0 Hz, 3H), 0.88-0.80 (m, 1H), 0.71 (s, 3H), 0.62 (s, 3H)

[0354] LCMS Rt=2.184 min (3.0 min chromatography), 10⁻⁸ AB₃ MIN E.M, purity 100%, C 23 H 37 O[M+H-H2O] + The MS ESI calculated value is 329, and the measured value is also 329.

[0355] Example 4. Synthesis of compounds 7, 8, 9, and 10. [ka]

[0356] Example 13. Synthesis of compounds 7 and 8. Part I

[0357] Step 1. To a suspension of PPh3EtBr (72.7g, 196mmol) in THF (200mL), t-BuOK (21.9g, 196mmol) was added at 10°C. The suspension turned dark red. After stirring at 40°C for 30 minutes, a solution of A5 (20g, 65.6mmol) in THF (20mL) was added at 40°C, and the reaction mixture was stirred at 40°C for 1 hour. This reaction mixture was poured onto 200g of crushed ice and stirred for 15 minutes. The organic layer was separated, and the aqueous phase was extracted with ELISA (2×200mL). The combined organic phases were washed with saturated brine (2×200mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by flash column (0-30% ELISA in PE) to obtain D1 (19.5g, 94%) as a solid.

[0358] 1 H NMR (400MHz, CDCl3) δ 5.20-5.01 (m, 1H), 3.70-3.50 (m, 1H), 2.48-2.15 (m, 3H), 1.89-1.52 (m, 8H), 1.52-1.09 (m, 7H), 1.09-0.93 (m, 5H), 0.93-0.70 (m, 11H).

[0359] Step 2. To a solution of D1 (10 g, 31.5 mmol) in anhydrous DCM (100 mL), silica gel (10 g) and PCC (13.5 g, 63.0 mmol) were added. This mixture was stirred at 15°C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by flash column (PE with 0-30% ethyl phosphate) to obtain D2 (6.6 g, 67%) as a solid.

[0360] 1 H NMR (400 MHz, CDCl3) δ 5.20-50.8 (m, 1H), 2.49-2.15 (m, 6H), 2.15-1.95 (m, 2H), 1.95-1.72 (m, 2H), 1.72-1.19 (m, 10H), 1.19-0.95 (m, 7H), 0.95-0.75 (m, 6H).

[0361] Step 3. Under a nitrogen atmosphere, anhydrous THF (100 mL) was cooled to 10°C, and anhydrous LiCl (3.54 g, 83.6 mmol) was added all at once. The mixture was stirred for 30 minutes to obtain a clear solution. Anhydrous FeCl3 (7.44 g, 45.9 mmol) was added all at once to this solution. The resulting mixture was stirred for another 30 minutes. The reaction mixture was cooled to -35°C, and methylmagnesium bromide (3 M in diethyl ether, 55.6 mL, 167 mmol) was added dropwise while maintaining the internal temperature between -35°C and -30°C. The above mixture was stirred at -30°C for 30 minutes. A solution of D2 (6.6 g, 20.9 mmol) in THF (20 mL) was added all at once. The internal temperature was raised to -20°C and maintained between -15°C and -20°C for 2 hours. The reaction mixture was poured into an ice-cold HCl aqueous solution (1 M, 200 mL) and extracted with ethyl acetate (2 × 200 mL). The combined organic layer was washed with water (200 mL), NaOH aqueous solution (10%, 2 × 200 mL), and brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / ethyl acetate = 20 / 1 to 20 / 1) to obtain D3 (6.5 g, 94%) as a colorless oil.

[0362] 1 H NMR (400 MHz, CDCl3) δ 5.15-5.05 (m, 1H), 2.42-2.11 (m, 3H), 1.90-1.40 (m, 16H), 1.40-1.10 (m, 5H), 1.10-0.81 (m, 10H), 0.81-0.69 (m, 3H).

[0363] Step 4. 9-BBN dimer (13.2g, 54.3 mmol) was added to a solution of D3 (6g, 18.1 mmol) in THF (85 mL). This mixture was stirred at 50°C for 2 hours. After cooling to 0°C, ethanol (10.3 mL, 181 mmol) and NaOH (36.1 mL, 5 M, 181 mmol) were added very slowly to the reaction mixture. After the addition, H2O2 (18.1 mL, 181 mmol, 30%) was slowly added, maintaining the internal temperature below 15°C. The resulting solution was stirred at 75°C for 1 hour. This mixture was cooled and added to water (100 mL). The aqueous phase was extracted with phenylethylamine (3 × 100 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain D4 (5.9 g, crude) as a colorless oil, which was used directly for the next step without purification.

[0364] Step 5. To the suspension of D4 (5.9 g, 16.9 mmol) in DCM (100 mL), silica gel (3 g) and PCC (5.45 g, 25.3 mmol) were added at 15°C. This mixture was stirred at 15°C for 2 hours. This mixture was filtered, and the filtered cake was obtained. The cake was washed with DCM (50 mL). The combined filtrate was concentrated under reduced pressure and purified by flash column (PE with 0-30% ethylacetate) to obtain D5 (4.3 g, impure) as a solid.

[0365] Step 6. To a solution of D5 (500 mg, 1.44 mmol) in MeOH (10 ml), HBr (57.4 mg, 0.29 mmol, 40% in water) and Br2 (337 mg, 2.15 mmol) were added at 25°C. This mixture was stirred at 25°C for 2 hours. The substance was quenched with saturated NaHCO3 aqueous solution (10 mL), treated with water (20 mL), and extracted with dimethyl (2 × 20 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain D6 (480 mg, crude) as a pale yellow oily substance, which was used directly for the next step.

[0366] 1 H NMR (400 MHz, CDCl3) δ 3.97-3.86 (m, 2H), 2.86-2.71 (m, 1H), 2.24-1.96 (m, 2H), 1.93-1.68 (m, 6H), 1.54-1.43 (m, 5H), 1.35-1.23 (m, 5H), 1.21-1.15 (m, 5H), 0.96-0.79 (m, 4H), 0.77-0.58 (m, 7H).

[0367] Step 7. To a solution of 1H-pyrazolo[3,4-c]pyridine (139 mg, 1.17 mmol) in THF (10 mL), NaH (89.5 g, 2.24 mmol, 60%) was added in fractions at 25°C. This mixture was stirred at 60°C for 10 minutes. Then, D6 (480 mg, 1.12 mmol) in THF (10 mL) was added dropwise to this solution. This mixture was stirred at 60°C for 1 hour. This mixture was poured into water (50 mL) and extracted with ELISA (3 × 20 mL). The combined organic layer was washed with brine (50 mL), dried over Na₂SO₄, and concentrated to obtain the crude product. The residue was purified by silica gel chromatography (100-200 mesh silica gel, petroleum ether / ethyl acetate = 0 / 1) to obtain a mixture of D7 and D8 (290 mg, crude) as a solid.

[0368] Step 8 (Compounds 9 and 10). D8 (290 mg, 0.62 mmol) was purified by SFC (column: OD (250 mm × 30 mm, 10 μm)), gradient: 40-40% B (A = 0.1% NH3 / H2O, B = EtOH), flow rate: 80 mL / min) to obtain pure compound 9 (48 mg, 16%) and pure compound 10 (18 mg, 6%) as solids.

[0369] Compound 9: 1 H NMR (400 MHz, CDCl3) δ 8.8 (s, 1H), 8.39-8.29 (m, 1H), 8.1 (s, 1H), 7.68-7.61 (d, J = 4.8 Hz, 1H), 5.32-5.19 (m, 2H), 2.76-2.62 (m, 1H), 2.27-2.06 (m, 2H), 1.84-1.67 (m, 4H), 1.53-1.26 (m, 11H), 1.23-1.09 (m, 7H), 1.08-1.01 (m, 1H), 0.96-0.89 (d, J = 7.2 Hz, 3H), 0.77 (s, 3H), 0.71 (s, 3H).

[0370] LCMS Rt=0.885 min (2 minute chromatography), 30-90AB_2MIN_E, purity 100%, C 29 H 42 N3O2[M+H] + MS ESI calculated value: 464, measured value: 464.

[0371] SFC Rt = 1.785 min (3 minute chromatography), OD-H_3UM_3_5_40_4ML_3MIN, purity: 100%.

[0372] Compound 10: 1 H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 8.39-8.28 (m, 1H), 8.09 (s, 1H), 7.69-7.61 (d, J = 4.8 Hz, 1H), 5.34-5.17 (m, 2H), 2.68-2.57 (m, 1H), 2.24-2.09 (m, 2H), 1.96-1.71 (m, 4H), 1.47-1.13 (m, 15H), 1.07-0.81 (m, 7H), 0.73 (s, 6H).

[0373] LCMS Rt=0.908 min (2 minutes chromatography), 30-90AB_2MIN_E, purity 98%, C 29 H 42 N3O2[M+H] + MS ESI calculated value: 464, measured value: 464.

[0374] SFC Rt = 2.132 mins (3 minutes of chromatography), OD-H_3UM_3_5_40_4ML_3MIN, purity: 99%.

[0375] Part II Step 1. To a solution of D5 (500 mg, 1.44 mmol) in MeOH (10 ml), HBr (57.4 mg, 0.288 mmol, 40% in water) and Br2 (229 mg, 1.46 mmol) were added at 25°C. This mixture was stirred at 25°C for 16 hours. This mixture was quenched with saturated NaHCO3 aqueous solution (10 mL), treated with water (20 mL), and extracted with siRNA (2 × 20 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain D6 (500 mg, crude) as a solid, which was used directly for the next step.

[0376] Step 2 (Compounds 7 and 8). 1H-pyrazolo[3,4-c]pyridine (1.45 mg, 1.22 mmol) was added at 25°C to a mixture of D6 (500 mg, 1.17 mmol) and K2CO3 (323 mg, 2.34 mmol) in acetone (3 mL). The mixture was stirred at 25°C for 12 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. This was then purified by preparative HPLC (column: Phenomenex Synergi C18 150 × 30 mm × 4 μm), gradient: 28-58% B (A = 0.1% HCl, B = ACN), flow rate: 30 mL / min), followed by SFC (column: OJ (250 mm × 30 mm, 10 μm), gradient: 35-35% B (A = 0.1% NH3H2O, B = ETOH), flow rate: 80 mL / min) to obtain compound 8 (15 mg, yield 75%) as a solid and compound 7 (5 mg, yield 25%) as a solid.

[0377] Compound 7: 1H NMR (400MHz, CDCl3) δ 9.26 (s, 1H), 8.27-8.17 (m, 1H), 7.98 (s, 1H), 7.58-7.49 (m, 1H), 5.32 (d, J = 16.0 Hz, 1H), 5.22 (d, J = 16.0 Hz, 1H), 2.62 (t, J = 8.0 Hz, 1H), 2.24-2.09 (m, 2H), 1.97-1.89 (m, 1H), 1.81-1.72 (m, 2H), 1.52-1.42 (m, 4H), 1.37-1.13 (m, 14H), 1.05-0.98 (m, 1H), 0.96 (d, J = 8.0 Hz, 3H), 0.90-0.82 (m, 1H), 0.74-0.71 (m, 6H).

[0378] LCMS Rt=2.406 minutes (in) (4.0 minutes of のクロマトグラフィー), 10-80AB.lcm, purity 99.3%, C 29 H 42 N3O2[M+H] + The MS ESI calculated value is 464 and the measured value is 464.

[0379] Compound 8: 1 H NMR (400MHz, CDCl3) δ 9.26 (s, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.98 (s, 1H), 7.52 (dd, J=1.0, 8.0 Hz, 1H), 5.32 (d, J = 16.0 Hz, 1H), 5.22 (d, J = 16.0 Hz, 1H), 2.67 (t, J = 8.0 Hz, 1H), 2.28-2.18 (m, 1H), 2.11-2.08 (m, 1H), 1.85-1.67 (m, 5H), 1.65-1.36 (m, 10H), 1.27-1.12 (m, 7H), 1.04 (br d, J=13.3 Hz, 1H), 0.93 (d, J = 8.0 Hz, 3H), 0.77 (s, 3H), 0.71 (s, 3H).

[0380] LCMS Rt = 2.358 min (in) (4.0 minute chromatography), 10⁻⁸⁰ AB⁻¹ cm, purity 99.7%, C 29 H 42 N3O2[M+H] + MS ESI calculated value: 464, measured value: 464.

[0381] Example 5. Synthesis of compound 11. [ka]

[0382] Step 1. To a solution of chloro(methoxymethyl)triphenylphosphoran (19.7 g, 57.7 mmol) in THF (200 mL), t-BuLi (44.3 mL, 57.7 mmol, 1.3 M in n-hexane) was added at -10°C, and the reaction mixture was stirred for 1 hour. Next, this mixture was added to A2 (20 g, 57.7 mmol) in THF (200 mL) at 0°C, and the reaction mixture was stirred at 15°C for 2 hours. This mixture was treated with NH4Cl (100 mL, 10%), and siRNA (2 × 200 mL) was added. The organic phase was separated and concentrated under reduced pressure to obtain the crude product. The residue was purified by flash column (0-30% siRNA in PE) to obtain E1 (5 g, 23%) as a solid.

[0383] 1 H NMR (400 MHz, CDCl3) δ 5.77 (s, 1H), 4.75-4.60 (m, 1H), 3.56 (s, 3H), 2.60-2.42 (m, 2H), 2.31-1.98 (m, 8H), 1.80-1.38 (m, 6H), 1.38-1.19 (m, 4H), 1.19-0.80 (m, 9H).

[0384] Step 2. To a solution of E1 (5 g, 13.3 mmol) in MeOH (50 mL), Pd-C (dried, 10%, 1 g) was added under N2 conditions. This suspension was degassed under reduced pressure and purged with H2 three times. The mixture was stirred at 15°C under H2 (15 psi) for 16 hours to obtain a black suspension. The reaction mixture was filtered through a Celite pad and washed with EtOH (3 × 20 mL). The filtrate was concentrated to obtain E2 (3.8 g, 76%) as a solid.

[0385] 1 H NMR (400 MHz, CDCl3) δ 4.78-4.60 (m, 1H), 3.42-3.35 (m, 1H), 3.35-3.28 (m, 4H), 2.50-2.38 (m, 1H), 2.20-1.95 (m, 5H), 1.85-1.60 (m, 7H), 1.60-1.18 (m, 8H), 1.18-0.91 (m, 2H), 0.91-0.76 (m, 7H).

[0386] Step 3. To a solution of E2 (3.8 g, 10.0 mmol) in MeOH (50 mL), K2CO3 (5.52 g, 40.0 mmol) was added all at once at 15°C under N2 conditions. This mixture was stirred at 15°C for 2 hours. Water (20 mL) was added. The aqueous phase was extracted with DCM (3 × 20 mL). The combined organic phase was washed with saturated brine (2 × 20 mL) and anhydrous Na2 The solution was dried with SO4, filtered, and concentrated to obtain E3 (3g, 90%) as a solid.

[0387] 1 H NMR (400 MHz, CDCl3) δ 3.68-3.51 (m, 1H), 3.51-3.39 (m, 1H), 3.35-3.28 (m, 4H), 2.50-2.38 (m, 1H), 2.20-2.01 (m, 2H), 1.85-1.70 (m, 5H), 1.70-1.46 (m, 5H), 1.46-1.12 (m, 7H), 1.12-0.91 (m, 1H), 0.91-0.70 (m, 7H).

[0388] Step 4. To a suspension of PPh3EtBr (11.5 g, 31.2 mmol) in THF (50 mL), t-BuOK (3.5 g, 31.2 mmol) was added at 10 °C. The suspension turned dark red. After stirring at 40 °C for 1 hour, a solution of E3 (3.5 g, 10.4 mmol) in THF (20 mL) was added at 40 °C, and the reaction mixture was stirred at 40 °C for 16 hours. A saturated NH4Cl solution (20 mL) was added to this mixture and extracted with SiO (2 × 20 mL). The organic layer was separated, and the aqueous phase was extracted with SiO (2 × 10 mL). The combined organic phases were washed with saturated brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by flash column (0-30% SiO in PE) to obtain E4 (1.5 g, 42%) as a solid.

[0389] 1 H NMR (400 MHz, CDCl3) δ 5.15-5.05 (m, 1H), 3.68-3.55 (m, 1H), 3.51-3.39 (m, 1H), 3.35-3.28 (m, 4H), 2.40-2.31 (m, 1H), 2.22-2.10 (m, 2H), 2.01-1.49 (m, 8H), 1.49-1.11 (m, 6H), 1.11-0.75 (m, 14H).

[0390] The stereochemistry of E4 at C7 was confirmed by NOE.

[0391] Step 5. To the suspension of E4 (1.5 g, 4.32 mmol) in DCM (30 mL), silica gel (2 g) and PCC (1.86 g, 8.64 mmol) were added at 15°C. This mixture was stirred at 15°C for 2 hours. This mixture was filtered, and the filtrate was washed with DCM (2 × 20 mL). The combined filtrate was concentrated under reduced pressure and purified by flash column (PE with 0-30% ethyl phosphate) to obtain crude product E5 (1.3 g, 87%) as a solid.

[0392] 1H NMR (400 MHz, CDCl3) δ 5.19-5.10 (m, 1H), 3.52-3.45 (m, 1H), 3.31-3.28 (m, 3H), 3.28-3.19 (m, 1H), 2.45-2.15 (m, 7H), 2.15-2.02 (m, 3H), 1.85-1.75 (m, 1H), 1.75-1.62 (m, 4H), 1.62-1.25 (m, 7H), 0.99 (s, 3H), 0.98-0.80 (m, 5H).

[0393] Step 6. Under a nitrogen atmosphere, anhydrous THF (20 mL) was cooled to 10°C, and anhydrous LiCl (589 mg, 13.9 mmol) was added all at once. The mixture was stirred for 30 minutes to obtain a clear solution. Anhydrous FeCl3 (1.24 g, 7.65 mmol) was added all at once to this solution. The resulting mixture was stirred for another 30 minutes. The reaction mixture was cooled to -35°C, and methylmagnesium bromide (9.26 mL, 27.8 mmol, 3 M in diethyl ether) was added dropwise while maintaining the internal temperature between -35°C and -30°C. The above mixture was stirred at -30°C for 30 minutes. E5 (1.2 g, 3.48 mmol) in THF (20 mL) was added all at once. The internal temperature was set to -20°C and maintained between -15°C and -20°C for 2 hours. The reaction mixture was poured into an ice-cold HCl aqueous solution (1 M, 20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layer was washed with water (20 mL), NaOH aqueous solution (10%, 2 × 20 mL), and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / ethyl acetate = 20 / 1 to 5 / 1) to obtain E6 (1 g, 80%) as a solid.

[0394] 1H NMR (400 MHz, CDCl3) δ 5.19-5.10 (m, 1H), 3.52-3.45 (m, 1H), 3.29 (s, 3H), 3.20-3.19 (m, 1H), 2.42-2.10 (m, 3H), 1.85-1.76 (m, 1H), 1.76-1.62 (m, 5H), 1.62-1.40 (m, 3H), 1.40-1.11 (m, 13H), 1.01-0.82 (m, 6H), 0.72 (s, 3H).

[0395] Step 7. To a solution of E6 (1 g, 2.77 mmol) in THF (15 mL), a solution of BH3-Me2S (2.77 mL, 27.7 mmol, 10 M in THF) was added dropwise at 0°C. This solution was stirred at 15°C for 3 hours. After cooling to 0°C, a solution of NaOH (16.6 mL, 2 M) was added very slowly. After the addition, H2O2 (2.76 mL, 27.7 mmol, 30% in water) was slowly added, maintaining the internal temperature below 10°C. The resulting solution was stirred at 15°C for 2 hours. Then, a saturated aqueous solution of Na2S2O3 (20 mL) was added until the reaction solution became clear. This mixture was extracted with SiO2 (3 × 20 mL). The combined organic solution was washed with saturated Na2S2O3 aqueous solution (2 × 10 mL) and brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain E7 (0.9 g, crude) as a solid, which was used in the next step without further purification.

[0396] Step 8. To the suspension of E7 (0.9 g, 1.37 mmol) in DCM (20 mL), silica gel (1 g) and PCC (1.02 g, 4.74 mmol) were added at 15°C. This mixture was stirred at 15°C for 2 hours. This mixture was filtered, and the filter cake was washed with DCM (2 × 20 mL). The combined filtrate was concentrated under reduced pressure and purified by flash column (PE with 0-20% ethyl phosphate). Recrystallization was performed in DCM / n-hexane (2 mL / 20 mL) at 15°C to obtain compound 11 (130 mg, 14%) as a solid.

[0397] 1H NMR (400 MHz, CDCl3) δ 3.45-3.38 (m, 1H), 3.29-3.20 (m, 4H), 2.55-2.45 (m, 1H), 2.19-2.09 (m, 4H), 2.05-1.85 (m, 2H), 1.75-1.55 (m, 2H), 1.55-1.35 (m, 9H), 1.35-1.15 (m, 10H), 0.94-0.82 (m, 1H), 0.72 (s, 3H), 0.63 (s, 3H).

[0398] LCMS Rt=1.134 min (2 minute chromatography), 30-90AB_2MIN_E, purity 87%, C 24 H 39 O2[M+H-H2O] + The MS ESI calculated value is 359, and the measured value is also 359.

[0399] HPLC Rt=4.54 min (8 minute chromatography), 30-90 AB 1.2 ml E.met, purity: 100%.

[0400] Example 6. Synthesis of compound 12. [ka]

[0401] Step 1. To a suspension of PPh3EtBr (26.5 g, 71.6 mmol) in THF (100 mL), t-BuOK (8.03 g, 71.6 mmol) was added at 10°C. The suspension turned dark red. After stirring at 40°C for 1 hour, a solution of E3 (8 g, 23.9 mmol) in THF (20 mL) was added at 40°C, and the reaction mixture was stirred at 40°C for 16 hours. A saturated NH4Cl solution (20 mL) and SiO (2 × 30 mL) were added to this mixture. The organic layer was separated, and the aqueous phase was extracted with SiO (2 × 30 mL). The combined organic phase was washed with saturated brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by flash column (PE with 0-20% SiO) to obtain F1 (2.1 g, 25%) as a colorless oil.

[0402] 1 H NMR (400 MHz, CDCl3) δ 5.15-5.05 (m, 1H), 3.68-3.55 (m, 1H), 3.40-3.35 (m, 1H), 3.31 (s, 3H), 2.43-2.32 (m, 1H), 2.22-2.10 (m, 2H), 2.01-1.89 (m, 1H), 1.89-1.50 (m, 8H), 1.50-1.22 (m, 9H), 1.10-0.82 (m, 11H).

[0403] The stereochemistry of F1 at C7 was confirmed by NOE.

[0404] Step 2. DMP (4.87 g, 11.5 mmol) was added to a solution of F1 (2 g, 5.77 mmol) in DCM (50 mL). The reaction mixture was then stirred at 15°C for 30 minutes. Saturated NaHCO3 aqueous solution (50 mL) and saturated Na2S2O3 aqueous solution (50 mL) were added to this reaction mixture and extracted with DCM (2 × 50 mL). The combined organic layer was washed with saturated NaHCO3 aqueous solution (2 × 20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain F2 (1.95 g, 98%) as a solid.

[0405] 1 H NMR (400 MHz, CDCl3) δ 5.19-5.10 (m, 1H), 3.50-3.35 (m, 2H), 3.30 (s, 3H), 2.46-2.15 (m, 7H), 2.15-1.98 (m, 3H), 1.78-1.50 (m, 9H), 1.50-1.21 (m, 4H), 1.05-1.12 (m, 4H), 0.89 (s, 3H).

[0406] Step 3. Under a nitrogen atmosphere, anhydrous THF (10 mL) was cooled to 10°C, and anhydrous LiCl (958 mg, 22.6 mmol) was added all at once. This mixture was stirred for 30 minutes to obtain a clear solution. Anhydrous FeCl3 (2.01 mg, 12.4 mmol) was added to this solution. The mixture was added all at once. The resulting mixture was stirred for a further 30 minutes. The reaction mixture was cooled to -35°C, and methylmagnesium bromide (15.0 mL, 45.2 mmol, 3 M in diethyl ether) was added dropwise while maintaining the internal temperature between -35°C and -30°C. The mixture was stirred at -30°C for 30 minutes. A solution of F2 (1.95 g, 5.65 mmol) in THF (10 mL) was added all at once. The internal temperature was reduced to -20°C and maintained between -15°C and -20°C for 2 hours. The reaction mixture was poured into ice-cold aqueous HCl (1 M, 20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with water (20 mL), aqueous NaOH (10%, 2 × 20 mL), and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified using a flash column (0-30% Â in PE) to obtain F3 (1.6g, 79%) as a solid.

[0407] 1 H NMR (400 MHz, CDCl3) δ 5.19-5.10 (m, 1H), 3.55-3.49 (m, 1H), 3.40-3.35 (m, 1H), 3.31 (s, 3H), 2.42-2.30 (m, 1H), 2.30-2.15 (m, 2H), 1.99-1.90 (m, 1H), 1.80-1.55 (m, 8H), 1.55-1.40 (m, 4H), 1.40-1.20 (m, 9H), 1.20-0.95 (m, 2H), 0.95-0.82 (m, 4H), 0.79 (s, 3H).

[0408] Step 3. To a solution of F3 (1.6 g, 4.43 mmol) in THF (25 mL), a solution of BH3-Me2S (4.43 mL, 44.3 mmol, 10 M in THF) was added dropwise at 0°C. This solution was stirred at 15°C for 3 hours. After cooling to 0°C, a solution of NaOH (26.5 mL, 53.1 mmol, 2 M) was added very slowly. After the addition, H2O2 (4.42 mL, 44.3 mmol, 30% in water) was slowly added, maintaining the internal temperature below 10°C. The resulting solution was stirred at 15°C for 2 hours. Then, a saturated aqueous solution of Na2S2O3 (20 mL) was added until the reaction solution became clear. This mixture was extracted with ELISA (3 × 20 mL). The combined organic solution was washed with saturated Na2S2O3 aqueous solution (2 × 10 mL) and brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain F4 (1.66 g, crude) as a solid, which was used in the next step without further purification.

[0409] Step 4. DMP (3.73 g, 8.80 mmol) was added at 15°C to a solution of F4 (1.66 g, 4.4 mmol) in DCM (50 mL). The reaction mixture was stirred at 15°C for 10 minutes. Saturated NaHCO3 aqueous solution (50 mL) and saturated Na2S2O3 aqueous solution (50 mL) were added to this reaction mixture and extracted with DCM (2 × 20 mL). The combined organic layer was washed with saturated NaHCO3 aqueous solution (3 × 20 mL) and brine (20 mL), dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography (PE / siRNA = 15 / 1 to 10 / 1) to obtain compound 12 (0.85 g, impure) as a solid. Compound 12 (0.2 g, impure) was recrystallized from MeCN (15 mL) at 15°C to obtain compound 12 (150 mg, 48%) as a solid.

[0410] 1H NMR (400 MHz, CDCl3) δ 3.58-3.50 (m, 1H), 3.45-3.35 (m, 1H), 3.32 (s, 3H), 2.55-2.48 (m, 1H), 2.21-2.05 (m, 4H), 2.01-1.85 (m, 2H), 1.85-1.60 (m, 5H), 1.60-1.45 (m, 4H), 1.45-1.20 (m, 12H), 1.10-1.01 (m, 1H), 0.77 (s, 3H),0.60 (s, 3H).

[0411] LCMS Rt=1.126 min (2 minute chromatography), 30-90AB_2MIN_E, purity 100%, C 24 H 39 O2[M+H-H2O] + The MS ESI calculated value is 359, and the measured value is also 359.

[0412] Example 7. Synthesis of compound 13. [ka]

[0413] Step 1. To a solution of compound 11 (300 mg, 0.796 mmol) in MeOH (10 ml), HBr (31.7 mg, 0.159 mmol, 40% in water) and Br2 (131 mg, 0.835 mmol) were added at 25°C. This mixture was stirred at 25°C for 16 hours and quenched by adding saturated NaHCO3 aqueous solution (10 mL) and water (20 mL). This mixture was extracted with ELISA (2 × 20 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain G1 (400 mg) as a solid, which was used directly for the next step.

[0414] 1H NMR (400MHz, CDCl3) δ 3.96-3.87 (m, 2H), 3.46-3.34 (m, 1H), 3.34-3.20 (m, 5H), 2.77 (t, J = 8 Hz, 1H), 2.23-2.06 (m, 1H), 1.98-1.83 (m, 2H), 1.80-1.61 (m, 3H), 1.49-1.40 (m, 5H), 1.38-1.19 (m, 12H), 0.91-0.82 (m, 1H), 0.74-0.64 (m, 6H).

[0415] Step 2. To a mixture of G1 (60 mg, 0.131 mmol) and K2CO3 (36.2 mg, 0.262 mmol) in acetone (5 mL), 1H-pyrazole-4-carbonitrile (18.2 mg, 0.196 mmol) was added at 25°C. The reaction mixture was stirred at 25°C for 16 hours and treated with H2O (50 mL). This mixture was extracted with  (3 × 50 mL). The combined organic solution was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified twice using a flash column (PE with 0-30% Â) to obtain compound 13 (15 mg, 25%) as a solid.

[0416] 1 H NMR (400MHz, CDCl3) δ 7.85 (s, 1H), 7.81 (s, 1H), 5.05-4.87 (m, 2H), 2.54 (m, 1H), 3.40-3.38 (m, 1H), 3.37-3.27 (m, 4H), 2.55 (d, J = 8 Hz, 1H), 2.23-2.15 (m, 1H), 2.041.96 (m, 1H), 1.76-1.72 (m, 2H), 1.52-1.49 (m, 8H), 1.32-1.21 (m, 10H), 1.11 (s, 1H), 0.88-0.85 (m, 1H), 0.73 (s, 3H), 0.69 (s, 3H).

[0417] LCMS Rt = 1.054 min (in) (2.0 minutes of chromatography), 30- 90AB_2MIN_E.M.lcm, 100% purity, C 28 H 42 N3O3[M+H] + The MS ESI calculated value is 468, and the measured value is also 468.

[0418] Example 8. Synthesis of compound 14. [ka]

[0419] Step 1. To a solution of compound 12 (700 mg, 1.85 mmol) in MeOH (10 ml), HBr (74 mg, 0.370 mmol, 40% in water) and Br2 (304 mg, 1.94 mmol) were added at 25°C. After stirring at 25°C for 16 hours, the mixture was quenched with saturated NaHCO3 aqueous solution (10 mL) and water (20 mL), and extracted with SiO2 (2 × 20 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain H1 (900 mg) as a solid, which was used directly for the next step.

[0420] 1 H NMR (400MHz, CDCl3) δ 3.92-3.88 (m, 2H), 3.58-3.46 (m, 1H), 3.41 (s, 3H), 3.37-3.27 (m, 3H), 2.84-2.80 (m, 1H), 1.91-1.89 (m, 2H), 1.78-1.65 (m, 3H), 1.54-1.40 (m, 5H), 1.40-1.17 (m, 12H), 0.91 (s, 1H), 0.79-0.75 (m, 3H), 0.62 (s, 3H).

[0421] Step 2. To a mixture of H1 (80 mg, 0.175 mmol) and K2CO3 (48.3 mg, 0.350 mmol) in acetone (5 mL), 1H-pyrazole-4-carbonitrile (24.3 mg, 0.262 mmol) was added at 25°C. The reaction mixture was stirred at 25°C for 16 hours, treated with H2O (50 mL), and extracted with  (3 × 50 mL). The combined organic solution was washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain the crude product, which was purified by flash column (PE with 0-30% Â) to obtain compound 14 (23 mg, 28%) as a solid.

[0422] 1 H NMR (400MHz, CDCl3) δ 7.83 (d, J = 18.8 Hz, 2H), 5.04-4.86 (m, 2H), 3.55-3.50 (m, 1H), 3.42-3.41 (m, 1H), 3.32 (s, 3H), 2.59 (t, J = 9.2 Hz, 1H), 2.27-2.14 (m, 1H), 2.03-1.98 (m, 1H), 1.95-1.83 (m, 2H), 1.80-1.64 (m, 4H), 1.53-1.47 (m, 3H), 1.45-1.23 (m, 9H), 1.20 (s, 3H), 1.14-1.00 (m, 2H), 0.78 (s, 3H), 0.65 (s, 3H).

[0423] LCMS Rt = 2.90 min (in) (4.0 minutes of chromatography), 10- 80AB.lcm, 100% purity, C 28 H 40 N3O2[M-H2O+H] + MS ESI calculated value: 450, measured value: 450.

[0424] Example 9. Synthesis of compounds 15, 16, and 17. [ka]

[0425] To a solution of G1 (200 mg, 0.439 mmol) in acetone (5 mL), 5-methoxy-2H-benzo[d][1,2,3]triazole (98.1 mg, 0.658 mmol) was added, followed by K2CO3 (121 mg, 0.878 mmol) at 25°C. The resulting reaction mixture was stirred at 25°C for 16 hours, treated with water (20 mL), and extracted with  (3 × 20 mL). The combined organic solution was washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain the crude product, which was purified by flash column (PE with 0-30% Â) to obtain impure compound 15 (50 mg). This impure compound 15 was purified by preparative HPLC separation (column: YMC-Actus Triart C18 150×30mm×5um), gradient: 65~95%B (A=water (0.05%HCl)-ACN, B=ACN), flow rate: 25mL / min) to obtain compound 15 (18mg, 8%) as a solid; a mixture of compound 16 and compound 17 (100mg, crude) was obtained. The mixture of compound 16 and compound 17 (100mg, crude) was purified by SFC separation (column: OJ (250mm×30mm, 5um)), gradient: 40~40%B (A=0.1%NH3H2O, B=ETOH), flow rate: 60mL / min) to obtain compound 16 (33mg, 14%) as a solid and compound 17 (16mg, 7%) as a solid.

[0426] Compound 15: 1 H NMR (400MHz, CDCl3) δ 7.73 (d, J = 8.0 Hz, 1H), 7.08-7.06 (m, 2H), 5.50-5.39 (m, 2H), 3.88 (s, 3H), 3.41-3.35 (m, 1H), 3.27 (s, 4H), 2.58 (t, J = 8.0 Hz, 1H), 2.27-2.07 (m, 2H), 2.01-1.88 (m, 1H), 1.81-1.69 (m, 2H), 1.53-1.47 (m, 5H), 1.46-1.12 (m, 14H), 0.94 - 0.82 (m, 1H), 0.76 (s, 3H), 0.74 (s, 3H).

[0427] LCMS Rt=3.240 minutes (4.0 minutes of のクロマトグラフィー), 10-80AB.lcm, purity 100%, C 31 H 46 N3O4[M+H] + The MS ESI calculated value is 524 and the measured value is 524.

[0428] Compound 16: 1 H NMR (400MHz, CDCl3) δ 7.92 (d, J = 8.0 Hz, 1H), 7.01 (dd, J = 4.0, 8.0 Hz, 1H), 6.60 (d, J = 4.0 Hz, 1H), 5.40-5.29 (m, 2H), 3.86 (s, 3H), 3.41-3.35 (m, 1H), 3.30-3.25 (m, 4H), 2.64 (t, J = 8.0 Hz, 1H), 2.28-2.09 (m, 2H), 2.00-1.90 (m, 1H), 1.76-1.75 (m, 2H), 1.54-1.43 (m, 7H), 1.42-1.20 (m, 11H), 1.13 (s, 1H), 0.92-0.87 (m, 1H), 0.75 (s, 3H), 0.74 (s, 3H).

[0429] LCMS Rt=3.025 minutes (4.0 minutes of のクロマトグラフィー), 10-80AB.lcm, purity 100%, C 31 H 46 N3O4[M+H] + The MS ESI calculated value is 524 and the measured value is 524.

[0430] Compound 17: 1H NMR (400MHz, CDCl3) δ 7.39 (d, J = 4.0 Hz, 1H), 7.24-7.13 (m, 2H), 5.43-5.32 (m, 2H), 3.89 (s, 3H), 3.39-3.37 (m, 1H), 3.27 (s, 4H), 2.63 (t, J = 12.0 Hz, 1H), 2.25-2.09 (m, 2H), 1.97-1.95 (m, 1H), 1.83-1.71 (m, 2H), 1.54-1.44 (m, 7H), 1.43-1.20 (m, 11H), 1.12 (s, 1H), 0.91-0.87 (m, 1H), 0.74 (s, 6H)

[0431] LCMS Rt=3.033 min (4.0 min chromatography), 10⁻⁸⁰ AB⁻¹ cm, purity 100%, C 31 H 46 N3O4[M+H] + The MS ESI calculated value is 524, and the measured value is also 524.

[0432] Example 10. Synthesis of compounds 18, 19, and 20. [ka]

[0433] To a solution of H1 (200 mg, 0.439 mmol) in acetone (5 mL), 5-methoxy-2H-benzo[d][1,2,3]triazole (98.1 mg, 0.658 mmol) was added, followed by K2CO3 (121 mg, 0.878 mmol) at 25°C. The resulting reaction mixture was stirred at 25°C for 16 hours, treated with water (20 mL), and extracted with siRNA (3 × 20 mL). The combined organic solution was washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain the crude product. This was purified by flash column (PE with 0-30% siRNA) to obtain compound 18 (10 mg, 4%) as a solid, and a mixture of compound 19 and compound 20 (100 mg, crude) was obtained. A mixture of compound 19 and compound 20 was purified by SFC separation (column: OD (250 mm × 30 mm, 5 μm)), gradient: 40-40% B (A = 0.1% NH3H2O, B = ETOH), flow rate: 50 mL / min) to obtain compound 19 (32 mg, 13%) as a solid, and compound 20 ( 27 mg (12%) was obtained as a solid.

[0434] Compound 18: 1 H NMR (400MHz, CDCl3) δ 7.74-7.71 (m, 1H), 7.08-7.06 (m, 2H), 5.48-5.38 (m, 2H), 3.88 (s, 3H), 3.55-3.50 (m, 1H), 3.42-3.38 (m, 1H), 3.32 (s, 3H), 2.64-2.60 (m, 1H), 2.29-2.18 (m, 1H), 2.14-2.06 (m, 1H), 1.92 (m, 1H), 1.68 (m, 5H), 1.53-1.41 (m, 4H), 1.41-1.19 (m, 12H), 1.09-1.02 (m, 1H), 0.79 (s, 3H), 0.73 (s, 3H)

[0435] LCMS Rt=3.215 min (4.0 min chromatography), 10⁻⁸⁰ AB₁⁻¹ cm, purity 100%, C 31 H 46N3O4[M+H] + The MS ESI calculated value is 524 and the measured value is 524.

[0436] Compound 19: 1 H NMR (400MHz, CDCl3) δ 7.92 (d, J = 8.0 Hz, 1H), 7.01 (m, 1H), 6.61-6.59 (m, 1H), 5.37-5.28 (m, 2H), 3.86 (s, 3H), 3.53 (t, J = 8.0 Hz, 1H), 3.43-3.37 (m, 1H), 3.32 (s, 3H), 2.68 (t, J = 8.0 Hz, 1H), 2.27-2.17 (m, 1H), 2.13-2.070 (m, 1H), 1.97-1.82 (m, 2H), 1.77-1.68 (m, 3H), 1.55-1.27 (m, 12H), 1.21 (s, 3H), 1.10-1.05 (m, 1H), 0.94 (s, 2H), 0.79 (s, 3H), 0.72 (s, 3H).

[0437] LCMS Rt=2.344 minutes (3.0 minutes of のクロマトグラフィー), 10-80AB.lcm, purity 96.15%, C 31 H 46 N3O4[M+H] + The MS ESI calculated value is 524 and the measured value is 524.

[0438] Compound 20: 1 H NMR (400MHz, CDCl3) δ 7.39 (d, J = 4.0 Hz, 1H), 7.23-7.11 (m, 2H), 5.36 (s, 2H), 3.89 (s, 3H), 3.53 (t, J = 8.0 Hz, 1H), 3.42-3.37 (m, 1H), 3.32 (s, 3H), 2.67 (t, J = 8.0 Hz, 1H), 2.26-2.17 (m, 1H), 2.12-2.06 (m, 1H), 1.97-1.81 (m, 2H), 1.77-1.67 (m, 3H), 1.55-1.46 (m, 4H), 1.46-1.22 (m, 9H), 1.21 (s, 3H), 1.12 (s, 1H), 1.09-1.02 (m, 1H), 0.79 (s, 3H), 0.71 (s, 3H).

[0439] LCMS Rt=1.095 min (2.0 min chromatography), 30-90AB_2MIN_E_M, purity 100%, C 31 H 46 N3O4[M+H] + The MS ESI calculated value is 524, and the measured value is also 524.

[0440] Example 11. Synthesis of compounds 21 and 22. [ka]

[0441] To a solution of G1 (150 mg, 0.329 mmol) and 1H-pyrazolo[3,4-c]pyridine (41 mg, 0.345 mmol) in acetone (3 mL), K2CO3 (26.1 g, 0.658 mmol) was added at 25°C. After stirring at 25°C for 10 hours, the mixture was poured into water (50 mL) and extracted with  (3 × 20 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. This was purified by preparative HPLC (column: YMC-Actus Triart C18 150 × 30 mm × 5 μm), gradient: 30-60% B (A = 0.1% HCl, B = ACN), flow rate: 25 mL / min) to obtain compound 22 (3 mg, impure) as a solid and compound 21 (20 mg, impure). Compound 21 (20 mg, impure) was purified by flash column (0-30% ethyl acetate in PE) to obtain compound 21 (9 mg, 6%) as a solid.

[0442] 1 H NMR (400MHz, CDCl3) δ 9.26 (s, 1H), 8.17 (d, J = 4.8 Hz, 1H), 7.98 (s, 1H), 7.53 (d, J = 6.8 Hz, 1H), 5.36-5.20 (m, 2H), 3.38-3.36 (m, 1H), 3.32-3.31 (m, 1H), 3.27 (s, 3H), 2.70-2.61 (m, 1H), 2.30-2.19 (m, 1H), 2.17-2.13 (m, 1H), 2.04-1.95 (m, 1H), 1.85-1.74 (m, 2H), 1.56-1.49 (m, 6H), 1.45-1.22 (m, 12H), 1.17-1.14 (m, 1H), 0.93-0.88 (m, 1st hour), 0.73 (s, 6th hour).

[0443] LCMS Rt=1.771 min (3.0 min chromatography), 10⁻⁸⁰AB, 100% purity, C 30 H 44 N3O3[M+H] + The MS ESI calculated value is 494, and the measured value is also 494.

[0444] Example 12. Synthesis of compounds 23 and 24. [ka]

[0445] A mixture of H1 (150 mg, 0.329 mmol) and K2CO3 (90.9 mg, 0.658 mmol) in acetone (3 mL) was mixed with 1H-pyrazolo[3,4-c]pyridine (41 mg, 0.345 mmol) at 25°C. After stirring at 25°C for 12 hours, the mixture was poured into water (50 mL) and extracted with  (3 × 20 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. This was purified by preparative HPLC (column: YMC-Actus Triart C18 150 × 30 mm × 5 μm), gradient: 35~65% B (A = 0.1% HCl, B = ACN), flow rate: 25 mL / min) to obtain compound 23 (50 mg, 31%) as a solid and compound 24 (20 mg, impure). Compound 24 (20 mg, impure) was purified by SFC separation (column: AD (250 mm × 30 mm, 10 μm)), gradient: 45-45%B (A = 0.1% NH3H2O, B = EtOH), flow rate: 80 mL / min) to obtain compound 24 (8 mg, 5%) as a solid.

[0446] Compound 23: 1 H NMR (400MHz, CDCl3) δ 8.79 (s, 1H), 8.34 (d, J = 5.6 Hz, 1H), 8.09 (s, 1H), 7.66-7.63 (m, 1H), 5.23-5.30 (m, 2H), 3.56-3.48 (m, 1H), 3.42-3.37 (m, 1H), 3.33 (s, 3H), 2.69-2.66 (m, 1H), 2.27-2.17 (m, 1H), 2.14-2.07 (m, 1H), 1.97-1.84 (m, 2H), 1.80-1.65 (m, 4H), 1.55-1.28 (m, 13H), 1.21 (s, 3H), 1.10-1.04 (m, 1H), 0.80 (s, 3H), 0.71 (s, 3H).

[0447] LCMS Rt=2.290 min (4.0 min chromatography), 10⁻⁸⁰AB, purity 99.1%, C 30 H 44 N3O3[M+H] + The MS ESI calculated value is 494, and the measured value is also 494.

[0448] Compound 24: 1 H NMR (400MHz, CDCl3) δ 9.26 (s, 1H), 8.17 (d, J = 6.4 Hz, 1H), 7.98 (s, 1H), 7.56-7.50 (m, 1H), 5.35-5.19 (m, 2H), 3.56-3.50 (m, 1 H), 3.44-3.39 (m, 1H), 3.33 (s, 3H), 2.66 (t, J = 8.8 Hz, 1H), 2.25-2.22 (m, 1H), 2.10-2.07 (m, 1H), 1.97-1.67 (m, 6H), 1.52-1.38 (m, 7H), 1.36-1.25 (m, 6H), 1.21 (s, 3H), 1.15-1.03 (m, 1H), 0.79 (s, 3H), 0.70 (s, 3H).

[0449] LCMS Rt=2.155 min (4.0 min chromatography), 10⁻⁸⁰AB, 100% purity, C 30 H 44 N3O3[M+H] + The MS ESI calculated value is 494, and the measured value is also 494.

[0450] Example 13. Synthesis of compound 25. [ka]

[0451] Step 1. To a solution of A2 (20 g, 57.7 mmol) in THF (100 mL), K-selectlide (57.7 mL, 57.7 mmol, 1 M in THF) was added dropwise at -70°C. The reaction mixture was stirred at -70°C for 2 hours. This mixture was quenched with saturated NH4Cl (20 mL) at -20°C and extracted with siRNA (3 × 50 mL). The combined organic phases were washed with brine (2 × 30 mL), dried over Na2SO4, filtered, concentrated, and purified by flash column (0-30% siRNA in PE) to obtain I1 (12.5 g, 62%) as a solid.

[0452] 1 H NMR (400 MHz, CDCl3) δ 4.75-4.65 (m, 1H), 4.02-3.90 (m, 1H), 2.51-2.40 (m, 1H), 2.22-2.01 (m, 1H), 1.98-1.40 (m, 15H), 1.40-1.08 (m, 7H), 1.08-0.78 (m, 6H).

[0453] Step 2. To a solution of I1 (12 g, 34.4 mmol) in DCM (100 mL), TBSOTf (11.8 mL, 51.6 mmol) and 2,6-dimethylpyridine (7.37 g, 68.8 mmol) were added in one step at 15°C. This mixture was refluxed at 15°C for 7 hours. Then, saturated NH4Cl (50 mL) was added to this reaction mixture. The aqueous phase was extracted with DCM (3 × 50 mL). The combined organic phases were washed with brine (2 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain a residue, which was purified by flash column (PE with 0-5% ethylacetal) to obtain I2 (8.35 g, crude) as an oily substance. This was combined with another batch of I2-A (7.5 g, crude, I2-A / I2 = 1 / 1) and used directly for the next step.

[0454] Step 3. PPh3EtBr (37.8g, 102mmol) in THF (100mL) To the suspension, t-BuOK (11.4 g, 102 mmol) was added at 10°C. The suspension turned dark red. After stirring at 40°C for 1 hour, a solution of I2 (15.85 g, crude, containing I2-A) in THF (20 mL) was added at 40°C, and the reaction mixture was stirred at 40°C for 16 hours. To this mixture, saturated NH4Cl solution (20 mL) and SiO (60 mL) were added. The organic layer was separated, and the aqueous phase was extracted with SiO (2 × 50 mL). The combined organic phases were washed with brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by flash column (0-20% SiO in PE) to obtain I3 (10 g, crude) as a colorless oil.

[0455] Step 4. To a solution of I3 (12 g, 27.7 mmol) in DCM (100 mL), DMP (23.4 g, 55.4 mmol) was added, followed by H2O (2.48 mg, 0.138 mmol). This reaction mixture was stirred at 15°C for 30 minutes. Saturated NaHCO3 aqueous solution (50 mL) and saturated Na2S2O3 aqueous solution (50 mL) were added to this reaction mixture and extracted with DCM (2 × 50 mL). The combined organic layer was washed with saturated NaHCO3 aqueous solution (2 × 20 mL) and brine (20 mL), dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by flash column (PE with 0-10% ethyl phosphate) to obtain I4 (6 g, 50%) as a solid.

[0456] 1 H NMR (400 MHz, CDCl3) δ 5.20-5.00 (m, 1H), 3.88 (s, 1H), 2.48-1.97 (m, 10H), 1.80-1.35 (m, 8H), 1.35-1.11 (m, 2H), 1.11-0.80 (m, 18H), 0.02 (s, 6H).

[0457] Step 5. Under a nitrogen atmosphere, anhydrous THF (20 mL) was cooled to 15°C, and anhydrous LiCl (2.35 g, 55.6 mmol) was added all at once. The mixture was stirred for 30 minutes to obtain a clear solution. Anhydrous FeCl3 (4.94 g, 30.5 mmol) was added all at once to this solution. The resulting mixture was stirred for another 30 minutes. The reaction mixture was cooled to -35°C, and methylmagnesium bromide (3 M, 37.0 mL, 111 mmol in diethyl ether) was added dropwise while maintaining the internal temperature between -35°C and -30°C. The above mixture was stirred at -30°C for 30 minutes. I4 (6 g, 13.9 mmol) in THF (20 mL) was added all at once. The internal temperature was set to 15°C, and the reaction mixture was stirred for 2 hours. The reaction mixture was poured into ice-cold aqueous HCl solution (1 M, 20 mL) and extracted with ELISA (2 × 20 mL). The combined organic layers were washed with water (20 mL), NaOH aqueous solution (10%, 2 × 20 mL), and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column (0-5% Â in PE) to obtain I5 (3.5 g, 56%) as a solid.

[0458] 1 H NMR (400 MHz, CDCl3) δ 5.15-5.00 (m, 1H), 3.87 (s, 1H), 2.41-2.00 (m, 4H), 1.80-1.49 (m, 7H), 1.49-1.25 (m, 7H), 1.25-1.08 (m, 6H), 1.08-0.81 (m, 14H), 0.81-0.69 (m, 4H), 0.05-0.01 (m, 6H).

[0459] Step 6. To a solution of I5 (3.5 g, 7.83 mmol) in THF (20 mL), BH3.Me2S (7.83 mL, 10 M, 78.3 mmol) was added dropwise at 0°C. The resulting solution was stirred at 15°C for 3 hours. After cooling to 0°C, an aqueous NaOH solution (46.9 mL, 93.9 mmol, 2 M) was added very slowly. After the addition, H2O2 (7.84 mL, 78.3 mmol, 30% in water) was slowly added, maintaining the internal temperature below 10°C. The resulting solution was stirred at 15°C for 1 hour. Then, a saturated aqueous Na2S2O3 solution (20 mL) was added until the reaction solution became clear. This mixture was extracted with ELISA (3 × 20 mL). The combined organic layers were washed with saturated Na2S2O3 aqueous solution (2 × 10 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain I6 (3.4 g, crude) as a solid, which was used in the next step without further purification. .

[0460] Step 7. To a solution of I6 (3.4 g, 7.31 mmol) in DCM (20 mL), DMP (6.19 g, 14.6 mmol) was added, followed by H2O (2.62 mg, 0.146 mmol). This reaction mixture was stirred at 15°C for 30 minutes. Saturated NaHCO3 aqueous solution (50 mL) and saturated Na2S2O3 aqueous solution (10 mL) were added to this reaction mixture. This mixture was extracted with DCM (2 × 20 mL). The combined organic layer was washed with saturated NaHCO3 (2 × 20 mL) and brine (20 mL), dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by flash column (PE with 0-10% ethyl phosphate) to obtain I7 (2.2 g, 65%) as a solid.

[0461] 1 H NMR (400 MHz, CDCl3) δ 3.83-3.80 (m, 1H), 2.59-2.50 (m, 1H), 2.21-1.90 (m, 6H), 1.78-1.49 (m, 9H), 1.49-1.09 (m, 12H), 0.90 (s, 9H), 0.73 (s, 3H), 0.58 (s, 3H), 0.06-0.01 (m, 6H).

[0462] Step 8. To a solution of I7 (1.80 g, 3.88 mmol) in CH3OH (50 mL), concentrated HCl (0.966 mL, 12 M) was added at 15 °C under N2 conditions. This mixture was stirred at 15 °C for 16 hours. Saturated NaHCO3 (5 mL) was added to this mixture and stirred for 20 minutes. The aqueous phase was extracted with toluene (3 × 50 mL). The combined organic phases were washed with brine (2 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain a solid. This solid was purified by flash column (PE with 0-70% toluene) to obtain compound 25 (1.20 g, impure) as a solid. Impure compound 25 (600 mg, impure) was ground with hexane (30 mL) at 68 °C to obtain compound 25 (510 mg, 64%) as a solid.

[0463] 1 H NMR (400 MHz, CDCl3) δ 3.85 (brs, 1H), 2.58-2.52 (m, 1H), 2.21-2.06 (m, 4H), 2.03-1.92 (m, 2H), 1.85-1.58 (m, 3H), 1.58-1.45 (m, 4H), 1.45-1.14 (m, 15H), 0.75 (s, 3H), 0.61 (s, 3H).

[0464] LCMS Rt=0.893 min (2.0 min chromatography), 30-90AB, 100% purity, C 22 H 33 O[M+H-2H2O] + MS ESI calculated value: 313, measured value: 313.

[0465] Example 14. Synthesis of compound 26. [ka]

[0466] Step 1. To a solution of compound 25 (497 mg, 1.42 mmol) in MeOH (10 ml), HBr (57.2 mg, 0.284 mmol, 40% in water) and Br2 (230 mg, 1.75 mmol) were added at 15°C. After stirring at 15°C for 4 hours, the mixture was quenched with NaHCO3 (10 mL), treated with water (20 mL), and extracted with SiO2 (3 × 20 mL). The combined organic phase was washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain J1 (600 mg, crude) as a solid.

[0467] 1 H NMR (400 MHz, CDCl3) δ 3.95-3.86 (m, 2H), 2.86-2.80 (m, 1H), 2.40-2.05 (m, 3H), 2.05-1.57 (m, 6H), 1.55-1.13 (m, 16H), 1.05-0.95 (m, 1H), 0.75 (s, 3H), 0.65-0.55 (m, 3H).

[0468] Step 2. To a suspension of TEA (35.2 mg, 0.348 mmol) and 1H-pyrazole-4-carbon (12.9 mg, 0.139 mmol) in DMF (5 mL), J1 (50 mg, 0.116 mmol) was added at 25 °C under N2 conditions. This mixture was stirred at 25 °C for 16 hours. This mixture was concentrated to obtain a pale yellow solid. This solid was purified by preparative HPLC (column: YMC-Actus Triart C18 100 × 30 mm × 5 μm; conditions: water (0.05% HCl)-ACN; gradient 53%~83% B; gradient time (min): 9.5) to obtain compound 26 (22 mg, 43%) as a solid.

[0469] 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.81 (s, 1H), 5.05-4.87 (m, 2H), 3.88-3.82 (m, 1H), 2.70-2.58 (m, 1H), 2.28-2.15 (m, 1H), 2.05-1.56 (m, 7H), 1.48-1.15 (m, 17H), 0.76 (s, 3H), 0.66 (s, 3H).

[0470] LCMS Rt=0.828 min (1.5 minute chromatography), 5-95AB, 100% purity, C 26 H 34 N3O[M+H-2H2O] + MS ESI calculated value: 404, measured value: 404.

[0471] Example 15. Synthesis of compounds 27 and 28. [ka] To a suspension of 2H-pyrazolo[3,4-c]py (125 mg, 1.05 mmol) and K2CO3 (193 mg, 1.40 mmol) in acetone (10 mL), J1 (300 mg, 0.701 mmol) was added at 15°C under N2 conditions. This mixture was stirred at 15°C for 16 hours. The mixture was filtered and concentrated to obtain a solid, which was purified by preparative HPLC (column: Xtimate C18 150 × 25 mm × 5 μm; conditions: water (0.05% HCl)-ACN; gradient 16%~41% B; gradient time (min): 9.5) to obtain compound 27 (8.00 mg, 2%) as a solid and compound 28 (6.00 mg, 2%) as a solid.

[0472] Compound 27: 1H NMR (400 MHz, CDCl3) δ 9.25 (s, 1H), 8.19-8.14 (m, 1H), 7.98 (s, 1H), 7.55-7.50 (m, 1H), 5.36-5.20 (m, 2H), 3.87-3.85 (m, 1H), 2.75-2.70 (m, 1H), 2.33-1.72 (m, 5H), 1.50-1.12 (m, 19H), 0.90-0.77 (m, 4H), 0.71 (s, 3H).

[0473] LCMS Rt=0.725 min (1.5 minute chromatography), 5-95AB, 100% purity, C 28 H 40 N3O3[M+H] + The MS ESI calculated value is 466, and the measured value is also 466.

[0474] Compound 28: 1 H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 8.36-8.32 (m, 1H), 8.09 (s, 1H), 7.65-7.60 (m, 1H), 5.32-5.20 (m, 2H), 3.87-3.85 (m, 1H), 2.75-2.68 (m, 1H), 2.33-1.68 (m, 7H), 1.50-1.18 (m, 18H), 0.77 (s, 3H), 0.72 (s, 3H).

[0475] LCMS Rt=0.748 min (1.5 minute chromatography), 5-95AB, 100% purity, C 28 H 40 N3O3[M+H] + The MS ESI calculated value is 466, and the measured value is also 466.

[0476] Example 16. Synthesis of compound 29. [ka]

[0477] Step 1. Imidazole (27.4 g, 403 mmol) and TBSCl (60.7 g, 403 mmol) were added at 25°C to a solution of A3 (82 g, 269 mmol) in DCM (500 mL). The reaction mixture was stirred at 25°C for 5 hours. The reaction mixture was concentrated under reduced pressure. The residue was ground in MeOH (500 mL) to obtain K1 (102 g, 91%) as a solid.

[0478] 1 H NMR (400 MHz, CDCl3) δ 3.62-3.50 (m, 1H), 2.65-2.29 (m, 4H), 2.20-2.01 (m, 2H), 1.85-1.63 (m, 6H), 1.56-1.38 (m, 6H), 1.26-0.93 (m, 5H), 0.92-0.80 (m, 12H), 0.04 (s, 6H).

[0479] Step 2. To a solution of K1 (25 g, 59.7 mmol) in THF (50 mL), L-selectlide (65.6 mL, 1 M in THF, 65.6 mmol) was added at -70°C under N2 conditions. The reaction mixture was stirred at -70°C for 5 hours. The reaction mixture was quenched with water (50 mL). The mixture was extracted with Depositphotos (3 × 150 mL). The combined organic phases were washed with saturated brine (2 × 150 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography (PE / Depositphotos = 30 / 1 to 3 / 1) to obtain K2 (16 g, crude) as a solid.

[0480] 1 H NMR (400 MHz, CDCl3) δ 3.97 (s, 1H), 3.64-3.52 (m, 1H), 2.52-2.38 (m, 1H), 2.18-1.97 (m, 2H), 1.86-1.43 (m, 11H), 1.42-1.13 (m, 6H), 1.08-0.96 (m, 1H), 0.93-0.79 (m, 15H), 0.044 (s, 6H).

[0481] Step 5. To a solution of EtPPh3Br (39.3g, 106 mmol) in THF (100 mL), t-BuOK (11.8g, 106 mmol) was added at 25°C under N2. The reaction mixture was stirred at 25°C for 0.5 hours. K2 (15g, 35.6 mmol) was added to this reaction mixture under N2. The reaction mixture was stirred at 50°C for 5 hours. The reaction mixture was quenched with water (50 mL). The mixture was extracted with Depositphotos (3 × 150 mL). The combined organic phases were washed with brine (2 × 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / Depositphotos = 30 / 1 to 10 / 1) to obtain K3 (5.5g, 36%) and K 3 (6g, crude) was obtained as a solid.

[0482] 1 H NMR (400 MHz, CDCl3) δ 5.19-5.05 (m, 1H), 3.88 (s, 1H), 3.63-3.52 (m, 1H), 2.45-2.17 (m, 3H), 1.79-1.51 (m, 10H), 1.51-1.23 (m, 10H), 1.10-0.99 (m, 1H), 0.91-0.83 (m, 12H), 0.83-0.78 (m, 3H), 0.07-0.02 (m, 6H).

[0483] Step 6. To a solution of K3 (5g, 11.5 mmol) in THF (50 mL), NaH (2.28 g, 60%, 57.4 mmol) was added at 0°C. The reaction mixture was stirred at 0°C under N2 for 0.5 hours. MeI (44 g, 309 mmol) was added to this reaction mixture at 0°C. The reaction mixture was stirred at 40°C for 20 hours. The reaction mixture was quenched with ice water (30 mL) and stirred for 20 minutes. The aqueous phase was extracted with Depositphotos (3 × 50 mL). The combined organic phases were washed with brine (2 × 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography (PE / Depositphotos = 50 / 1 to 10 / 1) to obtain K4 (1.8 g, 35%) as a solid.

[0484] 1 H NMR (400 MHz, CDCl3) δ 5.15-5.07 (m, 1H), 3.64-3.54 (m, 1H), 3.28 (s, 3H), 3.26-3.21 (m, 1H), 2.41-2.12 (m, 3H), 1.72-1.51 (m, 10H), 1.49-1.15 (m, 9H), 1.06-0.97 (m, 1H), 0.97-0.77 (m, 15H), 0.05 (s, 6H).

[0485] Step 7. To a solution of K4 (1.8 g, 4.02 mmol) in THF (30 mL), TBAF (12 mL, 1 M in THF, 12.0 mmol) was added at 25°C, and the reaction mixture was stirred at 40°C for 15 hours. The reaction mixture was quenched with water (20 mL), and the aqueous phase was extracted with SiO2 (3 × 50 mL). The combined organic phases were washed with brine (2 × 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was ground with water (40 mL) at 80°C to obtain K5 (1.6 g, crude) as a solid.

[0486] 1 H NMR (400 MHz, CDCl3) δ 5.13-5.03 (m, 1H), 3.64-3.50 (m, 1H), 3.26-3.20 (m, 4H), 2.40-2.10 (m, 3H), 1.84-1.73 (m, 1H), 1.68-1.58 (m, 14H), 1.35-1.14 (m, 5H), 1.11-1.03 (m, 1H), 0.86-0.81 (m, 6H).

[0487] Step 8. To a solution of K5 (1.3 g, 3.90 mmol) in DCM (20 mL), silica gel (4 g) and PCC (1.68 g, 7.8 mmol) were added at 25°C. This mixture was stirred at 25°C for 3 hours. This mixture was filtered through a silica gel pad, the solid was washed with toluene / DCM (30 / 30 mL), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / toluene = 10 / 1 to 1 / 1) to obtain K6 (1 g, 78%) as a solid.

[0488] 1 H NMR (400 MHz, CDCl3) δ 5.16-5.07 (m, 1H), 3.32-3.19 (m, 4H), 2.48-2.09 (m, 6H), 2.09-1.87 (m, 3H), 1.78-1.10 (m, 14H), 1.00 (s, 3H), 0.87 (s, 3H).

[0489] Step 9. Under a nitrogen atmosphere, anhydrous THF (30 mL) was cooled to 10°C, and anhydrous LiCl (508 mg, 12.0 mmol) was added all at once. This mixture was stirred for 30 minutes to obtain a clear solution. Anhydrous FeCl3 (1.07 g, 6.64 mmol) was added all at once to this solution. The resulting mixture was stirred for another 30 minutes. This reaction mixture was cooled to -35°C, and methylmagnesium bromide (8.03 mL, 3 M in ether, 24.1 mmol) was added dropwise while maintaining the internal temperature between -35°C and -30°C. The above mixture was stirred at -30°C for 30 minutes. K6 (1 g, 3.02 mmol) in THF (10 mL) mmol was added all at once. The internal temperature was set to -20°C and maintained between -15°C and -20°C for 2 hours. The reaction mixture was poured into ice-cold aqueous HCl (1 M, 50 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layer was washed with water (50 mL), aqueous NaOH (10%, 2 × 100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / ethyl acetate = 20 / 1 to 2 / 1) to obtain K7 (800 mg, 77%) as a solid.

[0490] 1 H NMR (400 MHz, CDCl3) δ 5.17-5.07 (m, 1H), 3.25 (s, 4H), 2.42-2.15 (m, 3H), 1.90-1.80 (m, 1H), 1.67-1.57 (m, 6H), 1.55-1.37 (m, 7H), 1.35-1.14 (m, 10H), 0.84 (s, 3H), 0.76(s, 3H).

[0491] Step 10. To a solution of K7 (0.8 g, 2.3 mmol) in THF (25 mL), BH3.Me2S (2.3 mL, 10 M in THF, 23 mmol) was slowly added at 0°C under N2. The reaction mixture was stirred at 25°C for 12 hours. After cooling the mixture to 0°C, NaOH solution (7.66 mL, 3 M in H2O, 23.0 mmol) was very slowly added to the mixture. After the addition was complete, H2O2 (2.6 g, 30%) was slowly added, and the internal temperature was maintained below 10°C. The mixture was stirred at 25°C for 2 hours. The resulting solution was extracted with ELISA (3 × 150 mL). The combined organic layers were washed with Na2S2O3 aqueous solution (40 mL) and brine (50 mL) and dried over Na2SO4. The mixture was filtered. The filtrate was concentrated under reduced pressure to obtain K8 (650 mg, crude) as a solid. This crude product was used in the next step without further purification.

[0492] Step 11. To a solution of K8 (0.65 g, 1.78 mmol) in DCM (20 mL), silica gel (1.71 g) and PCC (0.765 g, 3.56 mmol) were added at 25°C. The reaction mixture was stirred at 25°C for 4 hours. The solution was filtered, and the filter cake was washed with HCl (10 mL). The solution was filtered again, and the filter cake was washed with HCl (30 mL). The solution was concentrated in vacuum. The residue was purified by silica gel chromatography (PE / SiO₂ = 50 / 1~1 / 1) to obtain compound 29 (0.12 g, 19%) as a solid.

[0493] 1 H NMR (400 MHz, CDCl3) δ 3.26 (s, 3H), 3.24-3.19 (m, 1H), 2.62-2.54 (m, 1H), 2.12-2.14 (m, 1H), 2.11(s, 3H) , 2.03-1.84 (m, 2H), 1.74-1.59 (m, 5H), 1.56-1.35 (m, 7H), 1.32-1.11 (m, 9H), 0.75 (s, 3H), 0.59 (s, 3H).

[0494] LCMS Rt=0.991 min (2 minute chromatography), 30-90AB_ELSD, purity 97.6.0%, C 22 H 33 O[M-H2O-CH3OH] + MS ESI calculated value: 313, measured value: 313.

[0495] Example 17. Synthesis of compounds 30 and 31. [ka]

[0496] Step 1. LiAlH(t-BuO)3 (27.2g, 107mmol) was added at -70°C to a solution of K1 (15g, 35.8mmol) in THF (100mL), and the reaction mixture was stirred at -70°C for 5 hours. The reaction mixture was poured into ice water (50mL) and stirred for 20 minutes. The organic layer was separated. The aqueous phase was extracted with ethyl acetate (2×50mL). The combined organic phases were washed with saturated brine (2×30mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column (0-10% ethyl acetate in PE) to obtain L1 (8g, crude) as a solid.

[0497] 1 H NMR (400 MHz, CDCl3) δ 3.65-3.41 (m, 2H), 2.53-2.38 (m, 1H), 2.30-1.95 (m, 2H), 1.95-1.65 (m, 6H), 1.65-1.38 (m, 8H), 1.38-0.99 (m, 4H), 0.99-0.78 (m, 14H), 0.78-0.65 (m, 1H), 0.046 (m, 6H).

[0498] Step 2. To a solution of bromo(ethyl)triphenylphosphoran (28.2 g, 76.0 mmol) in THF (100 mL), t-BuOK (8.52 g, 76.0 mmol) was added at 25 °C. This mixture was heated to 60 °C and stirred for 1 hour. A solution of L1 (8 g, 19.0 mmol) in THF (20 mL) was added. This mixture was stirred at 60 °C for 16 hours. This mixture was treated with NH4Cl (50 mL, saturated aqueous solution). The organic layer was separated. The aqueous phase was extracted with ethyl acetate (2 × 50 mL). The combined organic phases were washed with saturated brine (2 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column (0-5% ethyl acetate in PE) to obtain L2 (5 g, 61%) as a solid.

[0499] 1 H NMR (400 MHz, CDCl3) δ 5.22-5.05 (m, 1H), 3.65-3.49 (m, 1H), 3.4 9-3.30 (m, 1H), 2.48-2.35 (m, 1H), 2.35-2.19 (m, 2H), 1.98-1.85 (m, 1H), 1.75-1.55 (m, 11H), 1.55-1.25 (m, 9H), 1.25-1.10 (m, 1H), 0.95-0.80 (m, 14H), 0.047 (s, 6H).

[0500] Step 3. To a solution of L2 (5g, 11.5 mmol) in THF (50 mL), NaH (2.28 g, 57.4 mmol, 60% in mineral oil) was added all at once at 0°C under N2. After 30 minutes, MeI (16.1 g, 114 mmol) was added dropwise at 20°C. The reaction mixture was stirred at 40°C for 6 hours. This mixture was quenched at 0°C with saturated NH4Cl aqueous solution (20 mL, saturated aqueous solution). The organic layer was separated. The aqueous phase was extracted with ELISA (2 × 20 mL). The combined organic phases were washed with saturated brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain L3 (5 g, crude) as a solid, which was used directly in the next step.

[0501] 1 H NMR (400 MHz, CDCl3) δ 5.20-5.10 (m, 1H), 3.60-3.55 (m, 1H), 3.28 (s, 3H), 2.90-2.75 (m, 1H), 2.41-2.05 (m, 3H), 1.85-1.35 (m, 14H), 1.35-1.00 (m, 6H), 1.00-0.65 (m, 15H), 0.05 (m, 6H).

[0502] Step 4. To a solution of L3 (5 g, 11.1 mmol) in THF (10 mL), TBAF (55.5 mL, 55.5 mmol, 1 M in THF) was added. This reaction mixture was stirred at 80°C for 16 hours. This reaction mixture was poured into water (50 mL). The organic layer was separated. The aqueous phase was extracted with ELISA (2 × 20 mL). The combined organic phases were washed with saturated brine (2 × 20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain L4 (3.6 g, impure) as a solid.

[0503] Step 5. To a solution of L4 (3.6 g, 10.8 mmol) in DCM (20 mL), silica gel (3 g) and PCC (4.64 g, 21.6 mmol) were added at 20°C. This mixture was stirred at 20°C for 2 hours. This mixture was filtered, and the filtered cake was washed with DCM (2 × 10 mL). The combined filtrate was concentrated under reduced pressure to obtain L5 (3 g, crude) as a solid.

[0504] Step 6. Under N2 conditions, anhydrous THF (10 mL) was cooled to 15°C, and anhydrous LiCl (1.53 g, 36.2 mmol) was added all at once. The mixture was stirred for 30 minutes to obtain a clear solution. Anhydrous FeCl3 (3.22 g, 19.9 mmol) was added all at once to this solution. The resulting mixture was stirred for another 30 minutes. The reaction mixture was cooled to -35°C, and methylmagnesium bromide (3 M in diethyl ether, 12.0 mL, 36.2 mmol) was added dropwise while maintaining the internal temperature between -35°C and -30°C. The above mixture was stirred at -30°C for 30 minutes. L5 (3 g, 9.07 mmol) in THF (10 mL) was added all at once. The internal temperature was raised to -20°C and maintained between -15°C and -20°C for 2 hours. The reaction mixture was poured into an ice-cold HCl aqueous solution (1 M, 20 mL) and extracted with ethyl acetate (2 × 20 mL). The organic layer was separated. The combined organic layers were washed with water (20 mL), NaOH aqueous solution (10%, 2 × 20 mL), and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column (0-10% ethyl acetate in PE) to obtain L6 (2.8 g, 89%) as a solid.

[0505] 1 H NMR (400 MHz, CDCl3) δ 5.20-5.00 (m, 1H), 3.27 (s, 3H), 2.90-2.80 (m, 1H), 2.45-2.10 (m, 4H), 2.90-1.45 (m, 11H), 1.45-1.05 (m, 11H), 0.95-0.72 (m, 7H).

[0506] Step 7. Add a solution of BH3.Me2S (8.07 mL, 10 M, 80.7 mmol) dropwise to a solution of L6 (2.8 g, 8.07 mmol) in THF (15 mL) at 0°C. The mixture was stirred at 15°C for 3 hours. After cooling to 0°C, NaOH solution (48.4 mL, 2 M, 96.8 mmol) was added very slowly. After the addition, H2O2 (8.07 mL, 80.7 mmol, 30% in water) was slowly added, and the internal temperature was maintained below 10°C. The resulting solution was stirred at 15°C for 2 hours. Then, saturated Na2S2O3 aqueous solution (20 mL) was added until the reaction solution became clear. This mixture was extracted with SiO2 (3 × 20 mL). The combined organic solution was washed with saturated Na2S2O3 aqueous solution (2 × 10 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain L7 (3.1 g, crude) as a solid, which was used in the next step without further purification.

[0507] Step 8. To a solution of L7 (3.1 g, 8.50 mmol) in DCM (20 mL), PCC (3.65 g, 17.0 mmol) and silica gel (3 g) were added at 25°C. This solution was stirred at 25°C for 3 hours. The reaction mixture was filtered, and the filter cake was washed with anhydrous DCM (2 × 20 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by flash column (PE with 0-20% ethyl phosphate) to obtain compound 30 (2 g, impure) as a solid. The residue, compound 30 (2 g, 5.51 mmol), was recrystallized in MeCN (20 mL) at 65°C to obtain compound 30 (24 mg, 1%, pure) as a solid. The mother liquor was concentrated to obtain compound 30 (1776 mg, impure) as a solid.

[0508] 1 H NMR (400 MHz, CDCl3) δ 3.26 (s, 3H), 2.90-2.80 (m, 1H), 2.50-2.41 (m, 1H), 2.20-2.08 (m, 4H), 2.08-1.95 (m, 1H), 1.82-1.70 (m, 2H), 1.70-1.60 (m, 3H), 1.60-1.45 (m, 5H), 1.45-1.20 (m, 9H), 1.20-1.05 (m, 2H), 0.90-0.80 (m, 1H), 0.76 (s, 3H), 0.62 (s, 3H).

[0509] LCMS t R = 0.905 min (2 minute chromatography), 30-90AB_ELSD, purity 100.0%, C 22 H 33 O[M-H2O-CH3O] + MS ESI calculated value: 313, measured value: 313.

[0510] Step 9. To a solution of compound 30 (200 mg, 551 μmol) in MeOH (10 mL), HBr (11.1 mg, 0.0551 mmol, 40% in water) and Br2 (105 mg, 0.661 mmol) were added at 25°C. This mixture was stirred at 25°C for 2 hours. This mixture was quenched with saturated NaHCO3 aqueous solution (10 mL) and treated with water (20 mL). This mixture was extracted with DCM (2 × 20 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain L8 (230 mg, crude) as a pale yellow oily substance, which was used directly in the next step without further purification.

[0511] Step 10. To a solution of L8 (230 mg, 0.521 mmol) in acetone (5 mL), K2CO3 (143 mg, 1.04 mmol) and 1H-pyrazole-4-carbonitrile (58.1 mg, 0.625 mmol) were added at 25°C. This mixture was stirred at 25°C for 16 hours. This mixture was treated with water (20 mL). This mixture was extracted with DCM (2 × 10 mL). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column (PE with 0-50% Â) to obtain compound 31 (63 mg, 27%) as a solid.

[0512] 1 H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.80 (s, 1H), 5.08-4.85 (m, 2H), 3.27 (s, 3H), 2.85-2.75 (m, 1H), 2.55-2.45 (m, 1H), 2.22-2.12 (m, 1H), 2.12-2.00 (m, 1H), 1.90-1.65 (m, 5H), 1.65-1.1.28 (m, 11H), 1.28-1.20 (m, 3H), 1.20-1.05 (m, 2H), 0.90-0.80(m, 1H), 0.77 (s, 3H), 0.68 (s, 3H).

[0513] LCMS t R = 0.912 min (2 minute chromatography), 30-90AB_ELSD, purity 100.0%, C 27 H 40 N3O3[M+H] + The MS ESI calculated value is 454, and the measured value is also 454.

[0514] Example 18. Synthesis of compounds 32 and 33. [ka]

[0515] Step 1. To a solution of compound 6 (1 g, 2.88 mmol) in MeOH (10 ml), HBr (0.1 mL, 40% in water) and Br2 (551 mg, 3.45 mmol) were added at 25°C. This mixture was stirred at 25°C for 3 hours. This mixture was quenched with saturated NaHCO3 aqueous solution (10 mL), treated with water (20 mL), and extracted with ELISA (2 × 30 mL). The combined organic phase was washed with saturated Na2S2O3 (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with (petroleum ether / ethyl acetate = 5 / 1) to obtain M1 (800 mg, 66%) as a solid.

[0516] 1 H NMR (400MHz, CDCl3) δ 3.95-3.88 (m, 2H), 2.76 (t, J = 8Hz, 1H), 2.20-2.11 (m, 1H), 1.95-1.84 (m, 2H), 1.78-1.67 (m, 2H), 1.53-1.43 (m, 4H), 1.42-1.38 (m, 1H), 1.34-1.08 (m, 13H), 1.03-0.93 (m, 4H), 0.87-0.80 (m, 1H), 0.71 (s, 3H), 0.65 (s, 3H).

[0517] Step 2. To a solution of M1 (200 mg, 0.47 mmol) in acetone (2 mL), K2CO3 (161 mg, 1.17 mmol) and 5-methyl-2H-tetrazole (59.2 mg, 0.705 mmol) were added. This mixture was stirred at 25°C for 16 hours. Water (10 mL) and ethyl acetate (20 mL) were added to this mixture. The organic layer was separated. The aqueous phase was extracted with ethyl acetate (50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 32 (56 mg, 28%) and compound 33 (82 mg, 41%) as solids.

[0518] Compound 32: 1 HNMR (400 MHz, CDCl3) δ 5.40-5.31 (m, 2H), 2.59-2.54 (m, 4H), 2.23-2.13 (m, 1H), 2.10-2.02 (m, 1H), 1.98-1.85 (m, 1H), 1.82-1.68 (m, 2H) , 1.54-1.39 (m, 5H), 1.37-1.15 (m, 13H), 1.04-0.94 (m, 4H), 0.90-0.81 (m, 1H), 0.72 (s, 6H).

[0519] LCMS Rt=1.103 min (2.0 min chromatography), 30-90AB, 100% purity, C 25 H 41 N4O2[M+H] + The MS ESI calculated value is 429, and the measured value is also 429.

[0520] Compound 33: 1 HNMR (400 MHz, CDCl3) δ 5.17-5.03 (m, 2H), 2.60 (t, J = 8Hz, 1H), 2.46 (s, 3H), 2.25-2.13 (m, 1H), 2.07-1.87 (m, 1H), 1.83-1.70 (m, 2H), 1.56-1.42 (m, 6H), 1.40-1.11 (m, 13H), 1.05-0.95 (m, 4H), 0.90-0.81 (m, 1H), 0.73 (s, 3H), 0.69 (s, 3H).

[0521] LCMS Rt=1.043 min (2.0 min chromatography), 30-90AB, 100% purity, C 25 H 41 N4O2[M+H] + The MS ESI calculated value is 429, and the measured value is also 429.

[0522] Example 19. Synthesis of compounds 34, 35, 36, and 37. [ka]

[0523] Step 1. To a solution of compound 5 (1.1 g, 3.17 mmol) in MeOH (20 mL), HBr (126 mg, 0.634 mmol, 40% in water) and Br2 (608 mg, 3.80 mmol) were added at 25°C. This mixture was stirred at 25°C for 1 hour. This mixture was quenched with saturated NaHCO3 (20 mL) and treated with water (20 mL). This mixture was extracted with DCM (2 × 30 mL). The combined organic phase was washed with brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain N3 (1.2 g, impure) as a solid, which was used directly for the next step.

[0524] 1 H NMR (400 MHz, CDCl3) δ 3.95-3.85 (m, 2H), 2.85-2.75 (m, 1H), 2.25-2.10 (m, 1H), 1.95-1.69 (m, 7H), 1.69-1.41 (m, 8H), 1.41-0.98 (m, 12H), 0.98-0.75 (m, 3H), 0.63 (s, 3H).

[0525] Step 2. In a solution of N3 (350 mg, 0.822 mmol) in acetone (10 mL) K2CO3 (226 mg, 1.64 mmol) and 5-methyl-2H-tetrazole (137 mg, 1.64 mmol) were added at 25°C. The mixture was stirred at 25°C for 16 hours. The reaction mixture was treated with water (20 mL). The mixture was extracted with CH2Cl2 (2 × 20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column (PE with 0-100% ethyl phosphate) to obtain compound 35 (5 mg, 1%) as a solid, compound 34 (49 mg, 14%) as a solid, compound 37 (6 mg, 2%) as a solid, and compound 36 (41 mg, 12%) as a solid.

[0526] Compound 34: 1 H NMR (400 MHz, CDCl3) δ 5.40-5.30 (m, 2H), 2.65-2.60 (m, 1H), 2.56 (s, 3H), 2.30-2.15 (m, 1H), 2.09-2.00 (m, 1H), 1.89-1.55 (m, 6H), 1.55-1.01 (m, 17H), 1.01-0.90 (m, 3H), 0.77 (s, 3H), 0.70 (s, 3H).

[0527] LCMS Rt=1.084 min (2 minute chromatography), 30-90AB_ELSD, purity 100.0%, C 25 H 41 N4O2[M+H] + The MS ESI calculated value is 429, and the measured value is also 429.

[0528] Compound 35: 1H NMR (400 MHz, CDCl3) δ 5.45-5.25 (m, 2H), 2.80-2.70 (m, 1H), 2.57 (s, 3H), 2.00-1.65 (m, 7H), 1.50-1.40 (m, 5H), 1.40-1.22 (m, 6H), 1.22-1.15 (m, 5H), 1.15-1.00 (m, 2H), 0.94 (s, 3H), 0.94-0.89 (m, 3H), 0.75 (s, 3H).

[0529] LCMS Rt=1.094 minutes (2 minutes of のクロマトグラフィー), 30-90AB_ELSD, purity 100.0%, C 25 H 39 N4O[M+H-H2O] + The MS ESI calculated value is 411 and the measured value is 411. Compound 36:

[0530] 1 H NMR (400 MHz, CDCl3) δ 5.20-5.00 (m, 2H), 2.70-2.60 (m, 1H), 2.47 (s, 3H), 2.25-2.15 (m, 1H), 2.10-2.00 (m, 1H), 1.90-1.65 (m, 5H), 1.65-1.25 (m, 10H), 1.25-1.11 (m, 7H), 1.11-1.05 (m, 1H), 1.05-0.95 (m, 3H), 0.77 (s, 3H), 0.67 (s, 3H).

[0531] LCMS Rt=1.007 minutes (2 minutes of のクロマトグラフィー), 30-90AB_ELSD, purity 100.0%, C 25 H 41 N4O2[M+H] + The MS ESI calculated value is 429 and the measured value is 429.

[0532] Compound 37: 1 H NMR (400 MHz, CDCl3) δ 5.30-5.20 (m, 1H), δ 5.00-4.90 (m, 1H), 2.90-2.80 (m, 1H), 2.48 (s, 3H), 1.95-1.65 (m, 7H), 1.45-1.40 (m, 3H), 1.40-1.22 (m, 7H), 1.22-1.10 (m, 6H), 1.10-1.06 (m, 2H), 0.97 (s, 3H), 0.96-0.93 (m, 3H), 0.75 (s, 3H).

[0533] LCMS Rt=1.021 min (2 minutes chromatography), 30-90AB_ELSD, purity 100.0%, C 25 H 39 N4O[M+H-H2O] + MS ESI calculated value: 411, measured value: 411.

[0534] Example 20. Synthesis of compounds 38 and 39. [ka]

[0535] Step 1. To a solution of D6 (500 mg, 1.17 mmol) in acetone (10 mL), K2CO3 (322 mg, 2.34 mmol) and 1H-pyrazole-4-carbonitrile (162 mg, 1.75 mmol) were added. After stirring at 25°C for 12 hours, the mixture was poured into water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layer was washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column (PE with 0-15% ethyl acetate) to obtain O1 (340 mg, 60%) as a solid.

[0536] 1H NMR (400 MHz, CDCl3) δ 7.99-7.78 (m, 2H), 5.07-4.84 (m, 2H), 2.67-2.49 (m, 1H), 2.26-2.13 (m, 1H), 2.02-1.81 (m, 2H), 1.64-1.38 (m, 10H), 1.34-0.99 (m, 12H), 0.98-0.91 (m, 3H), 0.76 (s, 2H), 0.72 (s, 1H), 0.69-0.63 (m, 3H).

[0537] Step 2. O1 (340 mg, 0.77 mmol) was purified by SFC (column: OD (250 mm × 30 mm, 5 μm)), gradient: 45-45%B (A = 0.1% NH3 / H2O, B = EtOH), flow rate: 50 mL / min) to obtain compound 38 (145 mg, 43%) and compound 39 (84 mg, 24%) as solids.

[0538] Compound 38: 1 H NMR (400 MHz, CDCl3) δ 7.88-7.78 (d, J = 19.2 Hz, 2H), 5.06-4.84 (m, 2H), 2.64-2.56 (m, 1H), 2.26-2.15 (m, 1H), 2.04-1.96 (m, 1H), 1.84-1.64 (m, 5H), 1.55-1.24 (m, 11H), 1.22-1.09 (m, 6H), 1.07-0.99 (m, 1H), 0.96-0.89 (m, 3H), 0.76 (s, 3H), 0.66 (s, 3H).

[0539] LCMS Rt=1.037 min (2 minutes chromatography), 30-90AB_2 MIN_E, 100% purity, C 27 H 40 N3O2[M+H] + The MS ESI calculated value is 438, and the measured value is also 438.

[0540] SFC Rt = 4.998 mins (10-minute chromatography), OD3EtOHDEA54025ML, purity: 99.8%.

[0541] Note: The structure of compound 38 was confirmed by X-ray.

[0542] Compound 39: 1 H NMR (400 MHz, CDCl3) δ 7.87-7.78 (d, J = 17.2 Hz, 2H), 5.07-4.86 (m, 2H), 2.57-2.49 (m, 1H), 2.23-2.13 (m, 1H), 2.06-1.99 (m, 1H), 1.97-1.86 (m, 1H), 1.79-1.67 (m, 2H), 1.55-1.36 (m, 6H), 1.35-1.13 (m, 12H), 1.05-0.92 (m, 4H), 0.89-0.81 (m, 1H), 0.72 (s, 3H), 0.68 (s, 3H).

[0543] LCMS Rt=1.051 min (2 minutes chromatography), 30-90AB_2MIN_E, purity 100%, C 27 H 39 N3O2Na[M+Na] + MS ESI calculated value: 460, measured value: 460.

[0544] SFC Rt = 6.270 mins (10-minute chromatography), OD3EtOHDEA54025ML, purity: 100%.

[0545] Example 21. Synthesis of compound 40. [ka]

[0546] Step 1. To a solution of P1 (2 g, 6.56 mmol) in toluene (20 mL), p-toluenesulfonic acid (20 mg, 0.116 mmol) and pyridine-2-ylmethaneamine (1.55 g, 14.4 mmol) were added at 25 °C. This reaction mixture was heated in a Dean-Stark apparatus at 130 °C for 16 hours. The reaction mixture was cooled to 25 °C and diluted with ELISA (30 mL). The organic layer was washed in the order of saturated NH4Cl (2 × 20 mL), saturated NaHCO3 (20 mL), and brine (20 mL), dried over Na2SO4, and then concentrated under reduced pressure to obtain crude product P2 (3 g, crude) as a yellow oil. It was used directly for the following purpose:

[0547] Step 2. P2 (1 g, 2.53 mmol), Cu(OTf)2 (1.18 g, 3.28 mmol), and sodium salt of L-ascorbic acid (1 g, 5.06 mmol) were added to a round-bottom flask under N2. Dry acetone (8 mL) and dry MeOH (8 mL) were added at 25°C and stirred for 5 minutes (the reaction mixture may turn brown). O2 was bubbled into the reaction mixture from a balloon for 5 minutes (a blue / green solution was obtained). The reaction mixture was then heated at 50°C for 1.5 hours under an O2 atmosphere. The reaction mixture was then cooled to 25°C, and ELISA (30 mL) and saturated Na4EDTA (30 mL, pH approximately 10) were added, and the reaction mixture was stirred for 1 hour. The layers were separated. The aqueous layer was extracted with Â(2 × 30 mL), dried over Na₂SO₄, and concentrated under reduced pressure to obtain the crude product. This was purified by silica gel column (PE / Â=3 / 1) to obtain P3 (230 mg, 28%) as a solid. This was then ground with MeCN(5 mL) at 25°C to obtain P3 (110 mg, 48% yield) as a solid and P3 (100 mg, impure) as a solid.

[0548] 1H NMR (400MHz, CDCl3) δ 3.78-3.73 (m, 1H), 2.98 (d, J = 1.4 Hz, 1H), 2.49-2.41 (m, 1H), 2.16-2.03 (m, 1H), 2.02-1.92 (m, 1H), 1.87-1.76 (m, 2H), 1.68-1.56 (m, 1H), 1.55-1.45 (m, 5H), 1.42-1.22 (m, 7H), 1.21 (s, 3H), 1.11 (s, 1H), 1.04-0.86 (m, 5H), 0.78 (s, 3H).

[0549] Step 3. t-BuOH (2 mL) and t-BuOK (348 mg, 3.11 mmol) were added to the over-dried bottom. This was degassed and packed with N2. A solution of P3 (100 mg, 0.312 mmol) in DME (2 mL) was added to the suspension. After 30 minutes, a solution of TosMIC (121 mg, 0.624 mmol) in DME (2 mL) was added. The mixture turned yellow. The resulting mixture was stirred at 25°C for 16 hours. Water was added, the mixture was stirred, and the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine. The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography using (petroleum ether / ethyl acetate = 4 / 1) to obtain compound 40 (60 mg, 58% yield) as a pale blue solid. This was then ground with MeCN (2 mL) to obtain compound 40 (30 mg) as a solid.

[0550] 1H NMR (400MHz, CDCl3) δ 3.51-3.44 (m, 1H), 2.46-2.37 (m, 1H), 2.23-2.11 (m, 1H), 2.00-1.91 (m, 1H), 1.84-1.74 (m, 2H), 1.70-7.67 (m, 1H), 1.62-1.57 (m, 1H), 1.53-1.31 (m, 8H), 1.30-1.22 (m, 4H), 1.21-1.15 (s, 3H), 1.09 (s, 1H), 1.04-0.84 (m, 6H), 0.77 (s, 3H)

[0551] LCMS Rt=0.747 min (2 minute chromatography), 30-90AB, 100% purity, C 21 H 30 N[M+H-2H2O] + The MS ESI calculated value is 296, and the measured value is also 296.

[0552] Note: The structure of compound 40 was confirmed by X-ray.

[0553] Example 23. Synthesis of compound 41. [ka]

[0554] Step 1. To a solution of P3 (1.2 g, 3.74 mmol) in THF (12 mL), KOH (632 mg, 11.3 mmol) and Me2SO4 (966 mg, 0.725 mL, 7.66 mol) were added at 0°C. The mixture was then heated to 25°C and stirred at the same temperature for 16 hours. The mixture was quenched by adding 50 mL of water and extracted with Depositphotos (2 × 30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (PE / Depositphotos = 10 / 1~5:1) to obtain Q1 (600 mg, 48%) as a solid and the starting material P3 (600 mg) as a solid.

[0555] 1H NMR (400MHz, CDCl3) δ 3.49 (s, 3H), 3.20-3.15 (m, 1H), 2.48-2.40 (m, 1H), 2.12-1.90 (m, 3H), 1.83-1.75 (m, 1H), 1.59-1.46 (m, 8H), 1.38-1.26 (m, 4H), 1.23-1.15 (m, 5H), 1.01-0.91 (m, 4H), 0.86-0.76 (m, 4H).

[0556] Step 2. t-BuOH (2 mL) and t-BuOK (334 mg, 2.98 mmol) were added to the over-dried bottom. This was evaporated and packed with N2. Q1 (100 mg, 0.299 mmol) in DME (1 mL) was added to the suspension. After 30 minutes, TosMIC (116 mg, 0.598 mmol) in DME (1 mL) was added. The mixture turned yellow. The resulting mixture was stirred at 25°C for 16 hours. Water was added and the mixture was stirred. This was then extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine. The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography using petroleum ether (ethyl acetate = 4 / 1) to obtain compound 41 (25 mg, impure) as a pale yellow oily substance. This was then ground with MeCN (1 mL) to obtain compound 41 (10 mg, 10%) as a solid.

[0557] 1 H NMR (400MHz, CDCl3) δ 3.41 (s, 3H), 2.92-2.88 (m, 1H), 2.43-2.35 (m, 1H), 2.23-2.09 (m, 1H), 2.02-1.89 (m, 2H), 1.81-1.64 (m, 2H), 1.49-1.32 (m, 5H), 1.27-1.24 (m, 5H), 1.22-1.20 (m, 4H), 1.00-0.85 (m, 7H), 0.83-0.79 (m, 1H), 0.77 (s, 3H).

[0558] LCMS Rt=0.903 min (2 minute chromatography), 30-90AB, 100% purity, C 22 H 32 N[M+H-2H2O] + The MS ESI calculated value is 296, and the measured value is also 296.

[0559] Example 24. Synthesis of compound 42. [ka]

[0560] Step 1. NaBH4 (46.9 mg, 1.24 mmol) was added at 25°C to a solution of P3 (200 mg, 0.624 mmol) in MeOH (5 mL). The reaction mixture was stirred at 25°C for 30 minutes. The reaction mixture was quenched with water (10 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain R1 (180 mg, crude) as a colorless oil, which was used directly for the next step without further purification.

[0561] Step 2. To a solution of R1 (200 mg, 0.620 mmol) in THF (3 mL), KOH (211 mg, 3.77 mmol) and Me2SO4 (320 mg, 0.24 mL, 2.54 mmol) were added at 0°C. The mixture was then heated to 25°C and stirred at the same temperature for 16 hours. The mixture was quenched by adding 50 mL of water and extracted with siRNA (2 × 30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column (PE / siRNA = 10 / 1~5:1) to obtain compound 42 (30 mg, 14%) as a solid. This was then ground with n-hexane (3 mL) at 25°C to obtain compound 42 (6 mg, 3%) as a solid.

[0562] 1H NMR (400MHz, CDCl3) δ 3.39-3.33 (m, 7H), 2.91-2.86 (m, 1H), 2.08-2.02 (m, 1H), 1.91-1.86 (m, 5H), 1.55-1.20 (m, 7H), 1.18-1.14 (m, 8H), 0.92-0.79 (m, 3H), 0.77 (s, 6H).

[0563] LCMS Rt=0.952 min (2 minute chromatography), 30-90AB, purity 99%, C 22 H 38 O3Na + [M+Na] + The MS ESI calculated value is 373, and the measured value is 373.

[0564] Example 25. Synthesis of compound 43. [ka]

[0565] Step 1. To a suspension of EtPPh3Br (3.32 g, 8.95 mmol) in THF (40 mL), t-BuOK (1 g, 8.95 mmol) was added at 25 °C under N2 conditions. After stirring at 60 °C for 30 minutes, a solution of Q1 (600 mg, 1.79 mmol) in THF (10 mL) was added at 60 °C. This mixture was stirred at 60 °C for 16 hours. This mixture was quenched with NH4Cl (80 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column (PE / siRNA = 10 / 1 to 5 / 1) to obtain S1 (340 mg, 55%) as a solid.

[0566] 1 H NMR (400MHz, CDCl3) δ 5.25-5.18 (m, 1H), 3.33 (s, 3H), 3.17-3.12 (m, 1H), 2.42-2.36 (m, 1H), 2.25-2.10 (m, 2H), 1.79-1.76 (m, 6H), 1.75-1.56 (m, 5H), 1.54-1.23 (m, 6H), 1.21-0.98 (m, 5H), 0.90-0.84 (m, 5H), 0.77 (s, 3H).

[0567] Step 2. To a solution of S1 (340 mg, 0.981 mmol) in THF (4 mL), 9-BBN dimer (597 mg, 2.45 mmol) was added at 0°C under N2. This solution was stirred at 60°C for 16 hours. After cooling to 0°C, solutions of EtOH (15 mL) and NaOH (1.96 mL, 5 M, 9.81 mmol) were added very slowly. After the addition, H2O2 (0.981 mL, 9.81 mmol, 30% in water) was slowly added, maintaining the internal temperature below 10°C. This mixture was stirred at 60°C under N2 for 1 hour. This mixture was cooled again to 30°C. Washing water (100 mL) was added to this solution. The mixture was added and extracted with toluene (2 × 50 mL). The combined organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain S₂ (400 mg, crude) as a colorless oil, which was used directly for the next step.

[0568] Step 3. To a solution of S2 (350 mg, 0.960 mmol) in DCM (10 mL), PCC (413 mg, 1.92 mmol) and silica gel (454 mg) were added at 25°C. This solution was then stirred at 25°C for 3 hours. The reaction mixture was filtered, and the residue was washed with anhydrous DCM (2 × 30 mL). The combined filtrate was concentrated under reduced p...

Claims

【Request Item 1】 【Chemistry 222】 【Chemistry 223】 【Chemistry 224】 【Chemistry 226】 【Chemistry 227】 【Chemistry 228】 A compound selected from the following. 【Request Item 2】 【Chemistry 229】 【Chemistry 230】 【Chemistry 231】 【Chemical 233】 【Chemistry 234】 【Chemical 235】 A pharmaceutically acceptable salt of a compound selected from the above.

3. A pharmaceutical composition comprising the compound according to Claim 1, or a pharmaceutically acceptable salt according to Claim 2, and a pharmaceutically acceptable excipient.

4. A composition for inducing sedation and / or anesthesia in a subject, comprising the compound according to claim 1, or a pharmaceutically acceptable salt according to claim 2.

5. The composition according to claim 4, wherein the composition is administered by intravenous, oral, or intramuscular administration.

6. The composition described above is the composition according to claim 4 or claim 5, which is administered chronically.

7. The composition according to any one of claims 4 to 6, wherein the subject is a mammal.

8. The composition according to any one of claims 4 to 7, wherein the subject is a human.

9. The composition according to any one of claims 4 to 8, which is administered in combination with another therapeutic agent.

10. A composition for treating seizures in a subject, comprising the compound described in claim 1, or a pharmaceutically acceptable salt described in claim 2.

11. A composition for treating epilepsy or status epilepticus in a subject, comprising the compound described in claim 1, or a pharmaceutically acceptable salt described in claim 2.

12. A composition for treating neuroendocrine disorders or dysfunctions in a subject, comprising the compound described in claim 1, or a pharmaceutically acceptable salt described in claim 2.

13. A composition for treating neurodegenerative diseases or disorders in a subject, comprising the compound described in claim 1, or a pharmaceutically acceptable salt described in claim 2.

14. A composition for treating motor impairment or tremor in a subject, comprising the compound described in claim 1, or a pharmaceutically acceptable salt described in claim 2.

15. A composition for treating mood disorders or anxiety disorders in a subject, comprising the compound described in claim 1, or a pharmaceutically acceptable salt described in claim 2.

16. A composition for treating a disorder related to GABA function in a subject, comprising the compound described in claim 1, or a pharmaceutically acceptable salt described in claim 2.

17. A composition for treating CNS-related disorders in a subject, comprising the compound described in claim 1, or a pharmaceutically acceptable salt described in claim 2.

18. The composition according to claim 17, 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, or tinnitus.

19. The composition according to claim 17, wherein the subject is a subject having Rett syndrome, fragile X syndrome, or Angelman syndrome.

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