C7, c12, and c16 substituted neuroactive steroids and methods for use thereof

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] Citation of Related Applications This application claims priority to U.S. Application No. 62 / 360,887, filed July 11, 2016, and U.S. Application No. 62 / 360,884, filed July 11, 2016, and U.S. Application No. 62 / 360,876, filed July 11, 2016, which are incorporated herein by reference. [Background technology]

[0002] background Brain excitability, defined as the level of alertness of an animal on a continuum ranging from coma to seizures, is controlled by various neurotransmitters. Generally, neurotransmitters are involved in controlling the conductance of ions across the neuronal membrane. At rest, the neuronal membrane has an electrical potential (or membrane voltage) of approximately -70 mV, with the interior of the cell being negative relative to the exterior. The electrical potential (voltage) is determined by the conductance of ions (K) across the neuronal semipermeable membrane. + , Na + , Cl - Neurotransmitters are stored in presynaptic vesicles and are released under the influence of a neuronal action potential. Upon release into the synaptic cleft, excitatory chemical transmitters such as acetylcholine cause membrane depolarization (a change in potential from -70 mV to -50 mV). This action is mediated by Na + It is mediated by postsynaptic nicotinic receptors stimulated by acetylcholine, which increases membrane permeability to ions. 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 effects on brain excitability are mediated by the neurotransmitter GABA. Because up to 40% of neurons in the brain utilize GABA as a neurotransmitter, GABA exerts a profound influence on global brain excitability. GABA controls the excitability of individual neurons by regulating chloride ion conductance across neuronal membranes. By interacting with recognition sites on the GRC, GABA promotes the flow of chloride ions into the cell down the GRC's electrochemical gradient. Elevated intracellular levels of this anion cause hyperpolarization of the transmembrane potential, reducing the neuron's sensitivity to excitatory inputs (i.e., reducing neuronal excitability). In other words, the higher the chloride ion concentration within a neuron, the lower the brain's excitability and arousal levels.

[0004] The GRC has been well documented to be involved in mediating anxiety, seizure activity, and sedation. Thus, GABA and drugs that act like or potentiate the actions of GABA (e.g., therapeutically useful barbiturates and benzodiazepines (BZs), e.g., Valium®) exert their therapeutically beneficial effects by interacting with specific regulatory sites on the GRC. Accumulating evidence now suggests that the GRC contains at least one distinct site for interaction with neuroactive steroids, in addition to the benzodiazepine and barbiturate binding sites. See, e.g., Lan, NC et al., Neurochem. Res. (1991) 16:347-356.

[0005] Neuroactive steroids can occur endogenously. The most potent endogenous neuroactive steroids are 3α-hydroxy-5-reduced pregnan-20-one and 3α-21-dihydroxy-5-reduced pregnan-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] There is a need for new and improved neurostimulatory steroids that act as modulators of brain excitability and as agents for the prevention and treatment of CNS-related diseases. The compounds, compositions and methods described herein are directed to this end. [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) Summary of the Invention [Means for solving the problem]

[0008] The compounds of the invention as described herein may, in certain embodiments, be used to treat, for example, GABA A These compounds act as GABA modulators, affecting the GABA receptor in either a positive or negative manner. A They are predicted to have central nervous system (CNS) activity as regulators of CNS excitability as mediated by their ability to modulate receptors.

[0009] Thus, in another aspect, there is provided a method of treating a CNS-related disorder in a subject in need thereof, 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 disorders, mood disorders, schizophrenia spectrum disorders, seizure disorders, memory and / or cognition disorders, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, 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.

[0010] In one aspect, provided herein is a method for treating a pulmonary arthritis, comprising: Formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is [ka] represents a single or double bond, where valence allows; R 2 , R 4 , R 6 , R 11a , and R 11b each independently represents hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, 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)2ORA1 where R A1 each instance of is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A1 groups are linked to form a heterocyclic or heteroaryl ring; R A2 is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R 11a and R 11b together to form oxo; R 3 is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; R 5 is absent or is hydrogen; [ka] represents a single or double bond, where [ka] If one of the is a double bond, the other [ka] is a single bond; [ka] If both are single bonds, R 5 is hydrogen; [ka] If one of the groups is a double bond, R 5 does not exist; R 17 is alkoxy, cyano, nitro, aryl, heteroaryl, or -C(O)R B1 , -C(O)CH2R B1, or -C(O)CH2CH2R B1 where R B1 is hydrogen, —OH, alkoxy, aryl, or heteroaryl; R 19 is hydrogen or alkyl; R 7 is halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, 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 or a pharmaceutically acceptable salt thereof.

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

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

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

[0014] In some embodiments, R 2 , R 4 , R 6 , R 11a , and R 11b are all hydrogen. In some embodiments, R 2 , R 4 , and R 6is independently halogen, C1-C6 alkyl, C1-C6 alkoxy, or —OH; in some embodiments, R 3 is C1-C6 alkyl (e.g., C1-C6 haloalkyl or -CH3).

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

[0016] In some embodiments, the compound of formula (I) has formula (II-c) or (II-d): [ka] In some embodiments, R 19 is -CH3. In some embodiments, R 7 is alkyl (e.g., unsubstituted alkyl or -CHOR A1 ) OR -OR A1 In some embodiments, R 7 is —CH, —CHCH, —OH, —OCH, or —CHOCH. In some embodiments, R 17 is —OCH, —CN, or —C(O)CH. 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 is alkoxy, cyano, or -C(O)R B1 Some fruits In the embodiment, R B1 is pyrazolyl (e.g., cyano-substituted pyrazolyl). In some embodiments, R B1 is tetrazolyl (e.g., methyl-substituted tetrazolyl). In some embodiments, R B1is a bicyclic heteroaryl (e.g., a methoxy-substituted bicyclic heteroaryl). B1 teeth, [ka] In some embodiments, R B1 teeth, [ka] is.

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

[0018] In some embodiments, R 11a and R 11b is independently hydrogen, C1-C6 alkyl (e.g., C1-C6 haloalkyl), C1-C6 alkoxy (e.g., C1-C6 alkoxyhalo), or —OH. 11a and R 11b taken together form oxo. In some embodiments, R 17 is C1-C6 alkoxy (e.g., —OCH3), cyano, or nitro. 19 is hydrogen or substituted or unsubstituted C1-C6 alkyl (e.g., -CH2OR X , where R X is hydrogen, C1-C6 alkyl, or C1-C6 alkoxy).

[0019] In some embodiments, the compound of formula (I) has formula (III-a) or (III-b): [ka] In some embodiments, the compound of formula (I) has formula (IV-a) or (IV-b): [ka] A compound of the formula In formula (IV-a) or (IV-b), m is 0, 1, or 2; n is 0, 1, or 2; R b each is independently hydrogen, halogen, or C1-C6 alkyl; R c is independently halogen, C1-C6 alkyl (e.g., —CH3 or C1-C6 haloalkyl), C1-C6 alkoxy, cyano, or —OH. In some embodiments, A is a 5-10 membered ring. In some embodiments, A is a fused bicyclic ring. In some embodiments, A is a monocyclic heteroaryl or a bicyclic heteroaryl.

[0020] In one aspect, provided is a compound of formula (V): [ka] or a pharmaceutically acceptable salt thereof, In formula (V), [ka] represents a single or double bond, where valence allows; R 2 , R 4 , R 6 , R 11a , and R 11b each independently represents hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , -N(RA1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 , -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 where R A1 each instance of is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A1 groups are linked to form a heterocyclic or heteroaryl ring; R A2 is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R 11a and R 11b together to form oxo; R 3 is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; R 5 is absent or is hydrogen; [ka] represents a single or double bond, where [ka] If one of the is a double bond, the other [ka] is a single bond; [ka] If both are single bonds, R 5 is hydrogen; [ka] If one of the groups is a double bond, R 5does not exist; R 17 is alkoxy, cyano, nitro, aryl, heteroaryl, -C(O)R B1 , -C(O)CH2R B1 , or -C(O)CH2CH2R B1 where R B1 is hydrogen, —OH, alkoxy, aryl, or heteroaryl; R 19 is hydrogen or alkyl; R 12 is halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, 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 or a pharmaceutically acceptable salt thereof.

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

[0022] In some embodiments, the compound of formula (V) has formula (Va) or (Vb): [ka] In some embodiments, R 2 , R 4 , R 6 , R 11a , and R 11b Each of R is independently hydrogen. 2 , R 4 , R 6 , R 11a , and R 11b are all hydrogen. In some embodiments, R 2 , R 4 , and R 6Each of R is independently halogen, C1-C6 alkyl, C1-C6 alkoxy, or —OH. 3 is C1-C6 alkyl (e.g., C1-C6 haloalkyl or -CH3). In some embodiments, the compound of formula (V) has formula (VI-a) or (VI-b): [ka] In some embodiments, the compound of formula (V) is a compound of formula (VI-c) or (VI-d): [ka] In some embodiments, R 19 is -CH3. In some embodiments, R 12 -OR A1 In some embodiments, R 12 is —CH, —CHCH, —OH, —OCH, or —CHOCH. In some embodiments, R 17 is —OCH, —CN, or —C(O)CH. 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 is alkoxy, cyano, or -C(O)R B1 is.

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

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

[0025] In some embodiments, R 11a and R 11b is independently hydrogen, C1-C6 alkyl (e.g., C1-C6 haloalkyl), C1-C6 alkoxy (e.g., C1-C6 haloalkoxy), or —OH. 11a and R 11b taken together form oxo. In some embodiments, R 17 is C1-C6 alkoxy (e.g., —OCH3) or cyano. In some embodiments, R 19 is hydrogen or substituted or unsubstituted C1-C6 alkyl (e.g., -CH2OR X , where R X is hydrogen, C1-C6 alkyl, or C1-C6 alkoxy). In some embodiments, the compound of formula (V) is represented by formula (VII-a) or (VII-b): [ka] is a compound of In formula (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) has formula (VIII-a) or (VIII-b): [ka] A compound of the formula In formula (VIII-a) or (VIII-b), m is 0, 1, or 2, n is 0, 1, or 2, and R b are each independently hydrogen, halogen, or C1-C6 alkyl; R c each is independently halogen, C1-C6 alkyl (eg, —CH3 or C1-C6 haloalkyl), C1-C6 alkoxy, cyano, or —OH.

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

[0027] In one aspect, provided herein is a compound of formula (IX): [ka] or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (IX): [ka] represents a single or double bond, where valence allows; R 2 , R 4 , R 6 , R 11a , and R 11b each independently represents hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, 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 where R A1each instance of is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A1 groups are linked to form a heterocyclic or heteroaryl ring; R A2 is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R 11a and R 11b together to form oxo; R 3 is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; R 5 is absent or is hydrogen; [ka] represents a single or double bond, where [ka] If one of the is a double bond, the other [ka] is a single bond; [ka] If both are single bonds, R 5 is hydrogen; [ka] If one of the groups is a double bond, R 5 does not exist; R 17 is alkoxy, cyano, nitro, aryl, heteroaryl, -C(O)R B1 , -C(O)CH2R B1, or -C(O)CH2CH2R B1 where R B1 is hydrogen, -OH, -N(R A1 )2, alkoxy, aryl, or heteroaryl; R 19 is hydrogen or alkyl; R 16 is halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, 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 or a pharmaceutically acceptable salt thereof.

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

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

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

[0031] In some embodiments, R 3 is C1-C6 alkyl (e.g., C1-C6 haloalkyl or -CH3).

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

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

[0034] In some embodiments, R 19 is -CH3. In some embodiments, R 16 is alkyl or -OR A1 In some embodiments, R 16 is —CH, —CHCH, —OH, —OCH, or —CH(CH). In some embodiments, R 17 is —OCH, —CN, or —C(O)CH. 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 is alkoxy, cyano, or -C(O)R B1 In some embodiments, R B1 is pyrazolyl (e.g., cyano-substituted pyrazolyl). In some embodiments, R B1 is tetrazolyl (e.g., methyl-substituted tetrazolyl). In some embodiments, R B1is a bicyclic heteroaryl (e.g., a methoxy-substituted bicyclic heteroaryl). B1 teeth, [ka] In some embodiments, R B1 teeth, [ka] is.

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

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

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

[0038] In some embodiments, R 19 is hydrogen or substituted or unsubstituted C1-C6 alkyl (e.g., -CH2OR X , where R X is hydrogen, C1-C6 alkyl, or C1-C6 alkoxy).

[0039] In some embodiments, the compound of formula (IX) has formula (Xa) or (Xb): [ka] A compound of the formula In formula (Xa) or (Xb), R a is hydrogen, halogen, C1-C6 alkyl (e.g., -CH3), or -OH.

[0040] In some embodiments, the compound of formula (IX) has formula (XI-a) or (XI-b): [ka] A compound of the formula In formula (XI-a) or (XI-b), m is 0, 1, or 2, n is 0, 1, or 2, and R b are each independently hydrogen, halogen, or C1-C6 alkyl; R c each is independently halogen, C1-C6 alkyl (eg, —CH3 or C1-C6 haloalkyl), C1-C6 alkoxy, cyano, or —OH.

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

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

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

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

[0045] In one aspect, an effective amount of a compound described herein (e.g., Formula (I), Formula (V) Provided herein are methods of administering to a subject in need thereof a compound of Formula (IX), or a compound of Formula (IX), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the compound, wherein the subject experiences sedation and / or anesthesia within two hours of administration. In some embodiments, the subject experiences sedation and / or anesthesia within one hour of administration. In some embodiments, the subject experiences immediate sedation and / or anesthesia. 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, hi some embodiments, the subject is a human.

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

[0048] In one aspect, provided herein is a method of treating seizures in a subject, the method comprising administering to the subject an effective amount of a compound described herein (e.g., a compound of Formula (I), Formula (V), or Formula (IX)).

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

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

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

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

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

[0054] In one aspect, provided herein is a method of treating a disorder associated with GABA function in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., a compound of Formula (I), Formula (V), or Formula (IX)), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the compound.

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

[0056] Thus, in another aspect, there is provided a method of treating a CNS-related disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound described herein (e.g., a compound of Formula (I), Formula (V), or Formula (IX)). In certain embodiments, the CNS-related disorder is selected from the group consisting of sleep disorders, mood disorders, schizophrenia spectrum disorders, seizure disorders, memory and / or cognitive disorders, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, 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 has Rett syndrome, Fragile X syndrome, or Angelman syndrome. In certain embodiments, for example, the following are provided: (Item 1) Formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is [ka] represents a single or double bond, where valence allows; R 2 , R 4 , R 6 , R 11a , and R 11b each independently represents hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, 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 where R A1each instance of is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A1 groups are linked to form a heterocyclic or heteroaryl ring; R A2 is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R 11a and R 11b together to form oxo; R 3 is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; R 5 is absent or is hydrogen; [ka] represents a single or double bond, where [ka] If one of the is a double bond, the other [ka] is a single bond; [ka] If both are single bonds, R 5 is hydrogen; [ka] If one of the groups is a double bond, R 5 does not exist; R 17 is alkoxy, cyano, nitro, aryl, heteroaryl, or -C(O)R B1 , -C(O)CH2R B1 , or -C(O)CH2CH2R B1where R B1 is hydrogen, —OH, alkoxy, aryl, or heteroaryl; R 19 is hydrogen or alkyl; R 7 is halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, 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 or a pharmaceutically acceptable salt thereof. (Item 2) The compound of formula (I) has formula (Ia) or (Ib): [ka] Item 1. The compound according to item 1, (Item 3) R 2 , R 4 , and R 6 , R 11a , and R 11b and each independently represents hydrogen. (Item 4) R 2 , R 4 , R 6 , R 11a , and R 11b The compound according to item 2, wherein all of are hydrogen. (Item 5) R 2 , R 4 , and R 6 each independently is halogen, C1-C6 alkyl, C1-C6 alkoxy, or -OH. (Item 6) R 3is C1-C6 alkyl (e.g., C1-C6 haloalkyl or -CH3). (Item 7) The compound of formula (I) may be a compound of formula (II-a) or (II-b): [ka] Item 3. The compound according to item 2, wherein the compound is (Item 8) The compound of formula (I) may be a compound of formula (II-c) or (II-d): [ka] Item 3. The compound according to item 2, wherein the compound is (Item 9) R 19 Item 9. The compound according to item 8, wherein is —CH3. (Item 10) R 7 Item 9. The compound according to item 8, wherein is -CH3, -CH2CH3, -OH, -OCH3, or -CH2OCH3. (Item 11) R 17 is —OCH3, —CN, or —C(O)CH3. (Item 12) R 17 is -C(O)CH2R C1 Item 9. The compound according to item 8, wherein (Item 13) R 17 is -C(O)CH2R B1 Item 9. The compound according to item 8, wherein (Item 14) R 17 is alkoxy, cyano, or -C(O)R B1 Item 9. The compound according to item 8, wherein (Item 15) R B1 is pyrazolyl (e.g., cyano-substituted pyrazolyl). (Item 16) R B1is tetrazolyl (e.g., methyl-substituted tetrazolyl). (Item 17) R B1 is a bicyclic heteroaryl (e.g., a methoxy-substituted bicyclic heteroaryl). (Item 18) R B1 teeth, [ka] Item 9. The compound according to item 8, wherein (Item 19) R B1 teeth, [ka] Item 9. The compound according to item 8, wherein (Item 20) R 6 is a halogen. (Item 21) R 6 is fluorine. (Item 22) R 11a and R 11b The compound according to item 2, wherein each of is independently hydrogen, C1-C6 alkyl (eg, C1-C6 haloalkyl), C1-C6 alkoxy (eg, C1-C6 alkoxyhalo), or —OH. (Item 23) R 11a and R 11b The compound according to item 2, wherein together form oxo. (Item 24) R 17 is C1-C6 alkoxy (for example, -OCH3), cyano, or nitro. (Item 25) R 19 is hydrogen or substituted or unsubstituted C1-C6 alkyl (e.g., -CH2OR X , where R Xis hydrogen, C1-C6 alkyl, or C1-C6 alkoxy. (Item 26) The compound of formula (I) may be represented by formula (IV-a) or (IV-b): [ka] The compound according to item 2, which is a compound of In formula (IV-a) or (IV-b), m is 0, 1, or 2; n is 0, 1, or 2; R b each is independently hydrogen, halogen, or C1-C6 alkyl; R c each is independently halogen, C1-C6 alkyl (e.g., —CH3 or C1-C6 haloalkyl), C1-C6 alkoxy, cyano, or —OH. (Item 27) The compound of formula (I) may be a compound of formula (III-a) or (III-b): [ka] The compound according to item 2, wherein in formula (III-a) or (III-b), R a is hydrogen, halogen, C1-C6 alkyl (e.g., -CH3), or -OH. (Item 28) The compound of formula (I) may be represented by formula (IV-a) or (IV-b): [ka] The compound according to item 2, wherein in formula (IV-a) or (IV-b), m is 0, 1, or 2; n is 0, 1, or 2; R b each is independently hydrogen, halogen, or C1-C6 alkyl; R ceach is independently halogen, C1-C6 alkyl (e.g., —CH3 or C1-C6 haloalkyl), C1-C6 alkoxy, cyano, or —OH. (Item 29) Item 16. The compound according to item 15, wherein A is a 5- to 10-membered ring. (Item 30) Item 16. The compound according to item 15, wherein A is a fused bicyclic ring. (Item 31) Item 16. The compound according to item 15, wherein A is a monocyclic heteroaryl or a bicyclic heteroaryl. (Item 32) Formula (V): [ka] or a pharmaceutically acceptable salt thereof, In formula (V), [ka] represents a single or double bond, where valence allows; R 2 , R 4 , R 6 , R 11a , and R 11b each independently represents hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, 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 where R A1 each instance of is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A1groups are linked to form a heterocyclic or heteroaryl ring; R A2 is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R 11a and R 11b together to form oxo; R 3 is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; R 5 is absent or is hydrogen; [ka] represents a single or double bond, where [ka] If one of the is a double bond, the other [ka] is a single bond; [ka] If both are single bonds, R 5 is hydrogen; [ka] If one of the groups is a double bond, R 5 does not exist; R 17 is alkoxy, cyano, nitro, aryl, heteroaryl, -C(O)R B1 , -C(O)CH2R B1 , or -C(O)CH2CH2R B1 where R B1 is hydrogen, —OH, alkoxy, aryl, or heteroaryl; R 19 is hydrogen or alkyl; R 12is halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, 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 or a pharmaceutically acceptable salt thereof. (Item 33) The compound of formula (V) has formula (Va) or (Vb): [ka] 33. The compound according to item 32, which is a compound of formula: (Item 34) R 2 , R 4 , R 6 , R 11a , and R 11b 34. The compound according to item 33, wherein each of R is independently hydrogen. 2 , R 4 , R 6 , R 11a , and R 11b are all hydrogen. (Item 35) R 2 , R 4 , and R 6 34. The compound according to item 33, wherein each of is independently halogen, C1-C6 alkyl, C1-C6 alkoxy, or —OH. (Item 36) R 3 34. The compound according to item 33, wherein is C1-C6 alkyl (e.g., C1-C6 haloalkyl or —CH3). (Item 37) The compound of formula (V) may be represented by formula (VI-a) or (VI-b): [ka] 34. The compound according to item 33, which is a compound of formula: (Item 38) The compound of formula (V) may be represented by formula (VI-c) or (VI-d): [ka] 34. The compound according to item 33, which is a compound of formula: (Item 39) R 19 Item 39. The compound according to item 38, wherein is —CH3. (Item 40) R 7 Item 39. The compound according to item 38, wherein is —CH3, —CH2CH3, —OH, —OCH3, or —CH2OCH3. (Item 41) R 17 Item 39. The compound according to item 38, wherein is —OCH3, —CN, or —C(O)CH3. (Item 42) R 17 is -C(O)CH2R C1 Item 39. The compound according to item 38, wherein (Item 43) R 17 is -C(O)CH2R B1 Item 39. The compound according to item 38, wherein (Item 44) R 17 is alkoxy, cyano, or -C(O)R B1 Item 39. The compound according to item 38, wherein (Item 45) R B1 39. The compound according to item 38, wherein is pyrazolyl (e.g., cyano-substituted pyrazolyl). (Item 46) R B1 is tetrazolyl (e.g., methyl-substituted tetrazolyl). (Item 47) R B1 39. The compound according to item 38, wherein: is a bicyclic heteroaryl (e.g., a methoxy-substituted bicyclic heteroaryl). (Item 48) R B1teeth, [ka] Item 39. The compound according to item 38, wherein (Item 49) R B1 teeth, [ka] Item 39. The compound according to item 38, wherein (Item 50) R 6 Item 34. The compound according to item 33, wherein is a halogen. (Item 51) R 6 Item 34. The compound according to item 33, wherein is fluorine. (Item 52) R 11a and R 11b 34. The compound according to item 33, wherein each of R is independently hydrogen, C1-C6 alkyl (e.g., C1-C6 haloalkyl), C1-C6 alkoxy (e.g., C1-C6 haloalkoxy), or —OH. 11a and R 11b together to form oxo. (Item 53) R 17 is C1-C6 alkoxy (for example, -OCH3) or cyano. (Item 54) R 19 is hydrogen or substituted or unsubstituted C1-C6 alkyl (e.g., -CH2OR X , where R X is hydrogen, C1-C6 alkyl, or C1-C6 alkoxy). (Item 55) The compound of formula (V) may be represented by formula (VII-a) or (VII-b): [ka] 34. The compound according to item 33, which is a compound of In formula (VII-a) or (VII-b), R a is hydrogen, halogen, C1-C6 alkyl (e.g., -CH3), or -OH. (Item 56) The compound of formula (V) may be represented by formula (VIII-a) or (VIII-b): [ka] 34. The compound according to item 33, which is a compound of In formula (VIII-a) or (VIII-b), m is 0, 1, or 2, n is 0, 1, or 2, and R b are each independently hydrogen, halogen, or C1-C6 alkyl; R c each is independently halogen, C1-C6 alkyl (e.g., —CH3 or C1-C6 haloalkyl), C1-C6 alkoxy, cyano, or —OH. (Item 57) 34. The compound according to item 33, wherein 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 a bicyclic heteroaryl. (Item 58) Formula (IX): [ka] or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (IX): [ka] represents a single or double bond, where valence allows; R 2 , R 4 , R 6 , R 11a , and R 11b each independently represents hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, 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 where R A1 each instance of is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A1 groups are linked to form a heterocyclic or heteroaryl ring; R A2 is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R 11a and R 11b together to form oxo; R 3 is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; R 5 is absent or is hydrogen; [ka] represents a single or double bond, where [ka] If one of the is a double bond, the other [ka] is a single bond; [ka] If both are single bonds, R 5 is hydrogen; [ka] If one of the groups is a double bond, R 5 does not exist; R 17 is alkoxy, cyano, nitro, aryl, heteroaryl, -C(O)R B1 , -C(O)CH2R B1 , or -C(O)CH2CH2R B1 where R B1 is hydrogen, -OH, -N(R A1 )2, alkoxy, aryl, or heteroaryl; R 19 is hydrogen or alkyl; R 16 is halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, 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 or a pharmaceutically acceptable salt thereof. (Item 59) The compound of formula (IX) may be represented by formula (IX-a) or (IX-b): [ka] 59. The compound according to item 58, which is a compound of formula: (Item 60) R 2 , R 4 , and R 6 , R 11a , and R 11b 59. The compound according to item 59, wherein each of R is independently hydrogen. 2 , R 4 , and R 6 , R 11a , and R 11b are all hydrogen. 2 , R 4 , and R6 Each of is independently halogen, C1-C6 alkyl, C1-C6 alkoxy, or -OH. (Item 61) R 3 59. The compound according to item 59, wherein is C1-C6 alkyl (e.g., C1-C6 haloalkyl or -CH3). (Item 62) The compound of formula (IX) may be represented by formula (Xa) or (Xb): [ka] 59. The compound according to claim 58, wherein (Item 63) The compound of formula (IX) may be represented by formula (Xc) or (Xd): [ka] 59. The compound according to claim 58, wherein (Item 64) R 19 Item 64. The compound according to item 63, wherein is —CH3. (Item 65) R 7 64. The compound according to item 63, wherein is -CH3, -CH2CH3, -OH, -OCH3, or -CH2OCH3. (Item 66) R 17 Item 64. The compound according to item 63, wherein is —OCH3, —CN, or —C(O)CH3. (Item 67) R 17 is -C(O)CH2R C1 64. The compound according to item 63, wherein (Item 68) R 17 is -C(O)CH2R B1 64. The compound according to item 63, wherein (Item 69) R 17 is alkoxy, cyano, or -C(O)R B1 64. The compound according to item 63, wherein (Item 70) RB1 is a pyrazolyl (e.g., cyano-substituted pyrazolyl). (Item 71) R B1 is tetrazolyl (e.g., methyl-substituted tetrazolyl). (Item 72) R B1 is a bicyclic heteroaryl (e.g., a methoxy-substituted bicyclic heteroaryl). (Item 73) R B1 teeth, [ka] 64. The compound according to item 63, wherein (Item 74) R B1 teeth, [ka] 64. The compound according to item 63, wherein (Item 75) R 6 59. The compound according to item 58, wherein R is halogen. 6 is fluorine. (Item 76) R 11a and R 11b 59. The compound of item 58, wherein each of R is independently hydrogen, C1-C6 alkyl (e.g., C1-C6 haloalkyl), C1-C6 alkoxy (e.g., C1-C6 haloalkoxy), or —OH. 11a and R 11b together to form oxo. (Item 77) R 17 59. The compound according to item 58, wherein is C1-C6 alkoxy (for example, —OCH3), cyano, or nitro. (Item 78) R 19 is hydrogen or substituted or unsubstituted C1-C6 alkyl (e.g., -CH2ORX , where R X is hydrogen, C1-C6 alkyl, C1-C6 alkoxy). (Item 79) The compound of formula (IX) may be represented by formula (Xa) or (Xb): [ka] 59. The compound according to item 58, which is a compound of In formula (Xa) or (Xb), R a is hydrogen, halogen, C1-C6 alkyl (e.g., -CH3), or -OH. (Item 80) The compound of formula (IX) may be represented by formula (XI-a) or (XI-b): [ka] 59. The compound according to item 58, which is a compound of In formula (XI-a) or (XI-b), m is 0, 1, or 2, n is 0, 1, or 2, and R b are each independently hydrogen, halogen, or C1-C6 alkyl; R c each is independently halogen, C1-C6 alkyl (e.g., —CH3 or C1-C6 haloalkyl), C1-C6 alkoxy, cyano, or —OH. (Item 81) 59. The compound according to item 58, wherein A is a 5-10 membered ring. In some embodiments, A is a fused bicyclic ring. In some embodiments, A is a monocyclic heteroaryl or bicyclic 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: (Item 83) [ka]

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[0058] definition chemical definition Definitions of specific functional groups and chemical terms are explained in detail below. Chemical elements are identified according to the Periodic Table of the Elements (CAS version, Handbook of Chemistry and Physics, 75th Edition, inside cover), and specific functional groups are generally defined as set forth therein. Furthermore, general rules of organic chemistry, as well as specific functional moieties and reactivities, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, NY, USA. New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd ed., Cambridge University Press, Cambridge, 1987.

[0059] Isomers (e.g., stereoisomers) can be separated by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC), supercritical fluid chromatography (SFC), and chiral salt formation. or the preferred isomer can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN 1972. The present invention further includes the compounds described herein as individual isomers substantially free of other isomers and alternatively as mixtures of various isomers.

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

[0061] As used herein, a pure enantiomer compound is substantially free of other enantiomers or stereoisomers of a compound (i.e., in enantiomeric excess). In other words, the "S" form of a compound is substantially free of the "R" form of the compound and is thus in enantiomeric excess of the "R" form. The terms "enantiomerically pure" or "pure enantiomer" mean that a compound contains more than 75%, more than 80%, more than 85%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 98.5%, more than 99%, more than 99.2%, more than 99.5%, more than 99.6%, more than 99.7%, more than 99.8%, 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 ingredients. For example, a pharmaceutical composition containing an enantiomerically pure R-compound may contain, for example, about 90% excipients and about 10% enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R-compound in such a composition may contain, for example, at least about 95% by weight of the R-compound and at most about 5% by weight of the S-compound, relative to the total weight of the compound. For example, a pharmaceutical composition containing an enantiomerically pure S-compound may contain, for example, about 90% excipients and about 10% enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S-compound in such a composition may contain, for example, at least about 95% by weight of the S-compound and at most about 5% by weight of the R-compound, relative to the total weight of the compound. In certain embodiments, the active ingredient may be formulated with a small amount of excipients or carriers, or may be formulated without excipients or carriers.

[0063] The articles "a" and "an" may be used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an analogue" means one analogue or more than one analogue.

[0064] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1~6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 , and C 5~6 is intended to encompass alkyl of the formula:

[0065] The following terms are intended to have the meanings provided below and are useful in understanding the specification and the intended scope of the invention.

[0066] "Alkyl" means the radical of a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1~20 In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C 1~12 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1~8 In some embodiments, an alkyl group has 1 to 6 carbon atoms (also referred to herein as "lower alkyl" or "C 1~6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1~5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C1~4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1~3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1~2 In some embodiments, the alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms. ("C 2~6 alkyl). C 1~6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), 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 the like. Unless otherwise specified, each occurrence of an alkyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents; for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1~10 In certain embodiments, the alkyl group is a substituted C 1~10 Common abbreviations for alkyl include Me(-CH), Et(-CHCH), iPr(-CH(CH)), nPr(-CHCHCH), n-Bu(-CHCHCHCHCH), or i-Bu(-CHCH(CH)).

[0067] "Alkenyl" refers to the radical of a straight- or branched-chain hydrocarbon group having 2 to 20 carbon atoms and one or more carbon-carbon double bonds and no carbon-carbon triple bonds ("C 2~20In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C 2~10 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, an alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., 2-butenyl) or terminal (e.g., 1-butenyl). C 2~4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), and butadienyl. (C4) and others. C 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each occurrence of an alkenyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2~10 In certain embodiments, the alkenyl group is a substituted C 2~10 It is alkenyl.

[0068] "Alkynyl" means a radical of a straight- or branched-chain hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more double bonds ("C 2~20 In some embodiments, an alkynyl group has 2 to 10 carbon atoms ("C 2~10 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2~4 alkynyl). In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, an alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (e.g., 2-butynyl) or terminal (e.g., 1-butynyl). C 2~4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 Alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Further examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each occurrence of an alkynyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents; for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C2~10 In certain embodiments, the alkynyl group is a substituted C 2~10 It is alkynyl.

[0069] "Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system ("C 6~14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 Aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an 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 point of attachment is on the aryl ring, and in such cases the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Aryl groups include, but are not limited to, phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each occurrence of an aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or with one or more substituents. ("substituted aryl"). In certain embodiments, the aryl group is substituted with unsubstituted C 6~14 In certain embodiments, the aryl group is a substituted C 6~14 It is aryl.

[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.

[0071] Representative examples of substituted aryl include: [ka] where R 56 and R 57 can be hydrogen, and R 56 and R 57 At least one of the following is independently selected from C1-C8 alkyl, C1-C8 haloalkyl, 4- to 10-membered heterocyclyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 , N.R. 58 SOR 59 , N.R. 58 SO2R 59 , COO alkyl, COO aryl, CONR 58 R 59 , C ONR 58 OR 59 , N.R. 58 R 59 , SO2NR 58 R 59 , S-alkyl, SO alkyl, SO alkyl, S aryl, SO aryl, SO aryl; or R 56 and R 57 may be linked to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms (optionally containing one or more heteroatoms selected from the group N, O, or S). R 60 and R 61 are independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, substituted C6-C 10 It is aryl, 5- to 10-membered heteroaryl or substituted 5- to 10-membered heteroaryl.

[0072] Other representative aryl groups having a fused heterocyclyl group include: [ka] where each W is C(R 66 )2, NR 66 , O, and S; and each Y is selected from carbonyl, NR 66 , O, and S; and R 66 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl.

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

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

[0075] "Hydroxy" or "hydroxyl," unless otherwise stated, by themselves or as part of another substituent, mean an --OH group.

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

[0077] "Heteroaryl" refers to a radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π-electrons shared in a cyclic arrangement) in which ring carbon atoms and 1 to 4 ring heteroatoms are provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, if valence allows. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, where the point of attachment is on the heteroaryl ring; in such cases, the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, where the point of attachment is on either the aryl ring or the heteroaryl ring, and in such cases the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups containing no heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on the ring containing the heteroatom (e.g., 2-indolyl) or on the ring without the heteroatom (e.g., 5-indolyl).

[0078] In some embodiments, heteroaryl groups are 5- to 10-membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, heteroaryl groups are 5- to 8-membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In some embodiments, heteroaryl groups are 5- to 6-membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heteroaryl"). In some embodiments, 5- to 6-membered heteroaryls have 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each occurrence of a heteroaryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, a heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, a heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0079] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0080] Representative examples of heteroaryls include those of the formula: [ka] wherein each Y is a carbonyl, N, NR65 , O and S; R 65 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5- to 10-membered heteroaryl.

[0081] "Carbocyclyl" or "carbocyclic" means a ring system having 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10 carbocyclyl). Exemplary C 3~6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. 3~8 The carbocyclyl group includes the above-mentioned C 3~6 Carbocyclyl groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl ( cyclooctyl (C), cyclooctenyl (C), bicyclo[2.2.1]heptanyl (C), bicyclo[2.2.2]octanyl (C), and the like. 3~10 The carbocyclyl group includes the above-mentioned C 3~8 Carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ) and the like. As the foregoing examples are illustrated, in certain embodiments, a carbocyclyl group is monocyclic ("monocyclic carbocyclyl") or contains a fused, bridged, or spiro ring system (e.g., a bicyclic system ("bicyclic carbocyclyl")), which may be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, where the point of attachment is on the carbocyclyl ring; in such cases, the number of carbons continues to refer to the number of carbons in the carbocyclyl ring system. Unless otherwise specified, each occurrence of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, a carbocyclyl group is an unsubstituted C 3~10 In certain embodiments, carbocyclyl The aryl group is a substituted C 3~10 It is a carbocyclyl.

[0082] In some embodiments, "carbocyclyl" refers to a monocyclic saturated carbocyclyl group having 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5~6 In some embodiments, a 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-mentioned C 5~6 Cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4). 3~8 Examples of cycloalkyl groups include the above-mentioned C 3~6 Cycloalkyl groups include cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each occurrence of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C 3~10 In certain embodiments, the cycloalkyl group is a substituted C 3~10 It is cycloalkyl.

[0083] "Heterocyclyl" or "heterocyclic" refers to the radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon or nitrogen atom, when valence allows. Heterocyclyl groups can be monocyclic ring systems ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems (e.g., bicyclic systems ("bicyclic heterocyclyl")), and can be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups, where the point of attachment is on the carbocyclyl or heterocyclyl ring, or on a ring system in which a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the heterocyclyl ring; in such cases, the number of ring members continues to refer to the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each occurrence of heterocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0084] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heterocyclyl"). In some embodiments, a 5- to 6-membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0085] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclic rings) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclic rings) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0086] Particular examples of heterocyclyl groups are shown in the following illustrative examples: [ka] Here, each W is 67 , C(R 67 )2, NR 67 , O, and S; each Y is selected from NR 67 , O and S; R 67 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 These heterocyclyl rings are acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (e.g., amido), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azide, carbo The alkyl group may be optionally substituted 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. Substituents include carbonyl or thiocarbonyl, which provide, for example, lactam and urea derivatives.

[0087] "Acyl" means -C(O)R 20 refers to the radical, where R 20is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein. "Alkanoyl" refers to a group in which R 20 is an acyl group where the aryl group is a group other than hydrogen. Representative acyl groups include formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), --C(O)-C1-C8 alkyl, and -C(O)-(CH2). t (C6-C 10 aryl), -C(O)-(CH2) t (5-10 membered heteroaryl), -C(O)-(CH2) t (C3-C 10 cycloalkyl) and -C(O)-(CH2) t (4- to 10-membered heterocyclyl) (t is an integer from 0 to 4). 21 is C1-C8 alkyl substituted with halo or hydroxy; or C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl (each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy).

[0088] "Acylamino" means -NR 22 C(O)R 23 refers to the radical, where R 22 and R 23Each occurrence of is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, as defined herein, or R 22 is an amino-protecting group. Exemplary "acylamino" groups include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino, and benzylcarbonylamino. Certain exemplary "acylamino" groups are -NR 24 C(O)-C1-C8 alkyl, -NR 24 C(O)-(CH2) t (C6~C 10 aryl), -NR 24 C(O)-(CH2) t (5-10 membered heteroaryl), -NR 24 C(O)-(CH2) t (C3~C 10 cycloalkyl) and -NR 24 C(O)-(CH2) t (4- to 10-membered heterocyclyl), where t is an integer from 0 to 4, and each R 24 independently represent hydrogen or C1-C8 alkyl. 25 is C1-C8 alkyl substituted with H, halo or hydroxy; C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, arylalkyl, 5-10 membered heteroaryl, or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; R 26 is C1-C8 alkyl substituted with H, halo or hydroxy; C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10aryl, arylalkyl, 5-10 membered heteroaryl, or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; provided that R 25 and R 26 Less One of them is not H.

[0089] "Acyloxy" means -OC(O)R 27 refers to the radical, where R 27 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, and benzylcarbonyl. In certain embodiments, R 28 is C1-C8 alkyl substituted with halo or hydroxy; C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy.

[0090] "Alkoxy" means -OR 29 refers to the group, where R 29is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e., having 1 to 6 carbon atoms. Further particular alkoxy groups have 1 to 4 carbon atoms.

[0091] In certain embodiments, R 29 is amino, substituted amino, C6-C 10 Aryl, aryloxy, carboxyl, cyano, C3-C 10 The "substituted alkoxy" group is a group having one or more substituents, for example, 1 to 5 substituents, particularly 1 to 3 substituents, and particularly 1 substituent, selected from the group consisting of cycloalkyl, 4- to 10-membered heterocyclyl, halogen, 5- to 10-membered heteroaryl, hydroxy, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2-, and aryl-S(O)2-. Exemplary "substituted alkoxy" groups include -O-(CH2) t (C6~C 10 aryl), -O-(CH2) t (5-10 membered heteroaryl), -O-(CH2) t (C3~C 10 cycloalkyl) and -O-(CH2) t(4-10 membered heterocyclyl), where t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present can itself be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. Particularly exemplary "substituted alkoxy" groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2.

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

[0093] "Substituted amino" refers to a group of the formula -N(R 38 )2, where R 38 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino protecting group, wherein R 38 At least one of R is not hydrogen. 38 are independently hydrogen, C1-C8 alkyl, C3-C8 alkenyl, C3 ~C8 alkynyl, C6~C 10 Aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl or C3-C 10 cycloalkyl; or C1-C8 alkyl substituted with halo or hydroxy; C3-C8 alkenyl substituted with halo or hydroxy; C3-C8 alkynyl substituted with halo or hydroxy, or -(CH2) t (C6~C 10 aryl), -(CH2) t (5-10 membered heteroaryl), -(CH2) t (C3~C 10 cycloalkyl) or -(CH2) t(4-10 membered heterocyclyl), where t is an integer from 0 to 8, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; or both R 38 The groups are linked to form an alkylene group.

[0094] Exemplary "substituted amino" groups include -NR 39 -C1-C8 alkyl, -NR 39 -(CH2) t (C6~C 10 aryl), -NR 39 -(CH2) t (5-10 membered heteroaryl), -NR 39 -(CH2) t (C3~C 10 cycloalkyl) and -NR 39 -(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, e.g., 1 or 2, and each R 39 independently represent hydrogen or C1-C8 alkyl; any alkyl group present may itself be substituted by halo, substituted or unsubstituted amino, or hydroxy; any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present may itself be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. For the avoidance of doubt, the term "substituted amino" includes alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino groups, as defined below. Substituted amino encompasses both mono- and di-substituted amino groups.

[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 a group consisting of -C(O)N(R 62 )2 radical, where each R 62 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino protecting group, wherein R 62 At least one of R is not hydrogen. 62 is H, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; or C1-C8 alkyl substituted with halo or hydroxy; or C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, or 5-10 membered heteroaryl, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; provided that at least one R 62 is other than H.

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

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

[0100] "Oxo" refers to =O.

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

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

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

[0104] As defined herein, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl groups). In general, the term "substituted," whether preceded by the term "optionally" or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that, when substituted, gives rise to a stable compound, e.g., a compound that does not undergo spontaneous transformation (e.g., by rearrangement, cyclization, elimination, or other reaction). Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when two or more positions in any given structure are substituted, the substituents may be the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, any substituents described herein that result in a stable compound. The present invention contemplates any and all such combinations to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents, as described herein, that satisfy the valence of the heteroatom and thereby form a stable moiety.

[0105] Exemplary carbon atom substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2、-CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-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 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R aa Each occurrence of C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R aagroups linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R bb Each occurrence of is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R bb groups linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R cc Each occurrence of is independently hydrogen, C 1~10Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R cc groups linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R dd Each occurrence of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -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 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R ee Each occurrence of C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group; Rff Each occurrence of is independently hydrogen, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, or two R ff groups linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R gg Each occurrence of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 Alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C 1~6 Alkyl)3 + X - , -NH(C 1~6 alkyl)2 + X - , -NH2(C 1~6 alkyl) + X - , -NH3 + X - , -N(OC 1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6 alkyl), -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 2~6Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl; - is the counter ion.

[0106] A "counterion" or "anionic counterion" is a negatively charged group that associates with a cationic quaternary amino group to maintain electroneutrality. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HSO4 - , sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.) and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0107] Nitrogen atoms may be substituted or unsubstituted, where valence allows, and may include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc)2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl and 5-14 membered heteroaryl, or two R cc The groups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd substituted with R aa , R bb , R cc and R dd 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). Amino protecting groups include -OH, -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 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 and 5- to 14-membered heteroaryl groups, where each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd group, and where R aa , R bb , R cc and R dd is as defined herein. Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Butts, 3rd Edition, John Wiley & Sons, 1999 (incorporated herein by reference).

[0109] Exemplary amino protecting groups include amide groups (e.g., —C(═O)R aa ) (including, but not limited to, formamide and acetamide); carbamate groups (e.g., —C(═O)OR aa ) (including, but not limited to, 9-fluorenylmethylcarbamate (Fmoc), t-butylcarbamate (BOC), and benzylcarbamate (Cbz); sulfonamide groups (e.g., —S(═O)R aa ) (including but 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 referred to as a hydroxyl protecting group). 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, and R aa , R bb , and R cc is as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Butts, 3rd Edition, John Wiley & Sons, 1999 (incorporated herein by reference).

[0111] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), 2-methoxyethoxymethyl (MEM), benzyl (Bn), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS), t-butylmethoxyphenylsilyl (TBMPS), methanesulfonate (mesylate), and tosylate (Ts).

[0112] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a thiol protecting group). 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, where R aa , R bb , and R cc is as defined herein. Sulfur protecting groups are well known in the art and Groups in Organic Synthesis, TW Greene and PG M Butts, 3rd Edition, John Wiley & Sons, 1999 (incorporated herein by reference).

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

[0114] Other definitions As used herein, the term "modulation" refers to the inhibition or potentiation of GABA receptor function. A "modulator" (e.g., a modulator compound) can be, for example, an agonist, partial agonist, antagonist, or partial antagonist of a GABA receptor.

[0115] "Pharmaceutically acceptable" means approved or approvable by a regulatory authority of a federal or state government, or a corresponding authority in a country other than the United States, or listed in the United States Pharmacopoeia or other generally recognized pharmacopoeia for use in animals (more specifically, humans).

[0116] "Pharmaceutically acceptable salts" refers to salts of compounds of the present invention that are pharmaceutically acceptable and that possess the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be inorganic or organic acid addition salts and inorganic or organic base addition salts. Specifically, such salts include (1) salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or salts formed 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-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphor or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or when coordinated with an organic base, e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.; and, if the compound contains a basic functional group, salts of non-toxic organic or inorganic acids, e.g., hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion of an acidic functional group. Such cations are exemplified by sodium cation, potassium cation, calcium cation, magnesium cation, ammonium cation, tetraalkylammonium cation, etc. See, e.g., Berge et al., J. Pharm. Sci. (1977) 66(1):1-79.

[0117] "Solvate" refers to a form of a compound that is associated with a solvent or water (also referred to as a "hydrate"), usually through a solvolysis reaction. This physical association involves hydrogen bonding. Conventional solvents include water, ethanol, acetic acid, and the like. The compounds of the present invention may be prepared, for example, in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric and non-stoichiometric solvates. In certain instances, a solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0118] "Stereoisomers": It should also be understood that compounds that have the same molecular formula but differ in the nature or bonding sequence of their atoms or in the arrangement of their atoms in space are referred to as "isomers." Isomers that differ in the arrangement of their atoms in space are referred to as "stereoisomers." Stereoisomers that are not mirror images of each other are referred to as "diastereomers," and those that are non-superimposable mirror images of each other are referred to as "enantiomers." For example, if a compound has an asymmetric 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 represented by the R and S ordering rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., (+) or (-)-isomer, respectively). Chiral compounds can exist as either individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0119] "Tautomers" refer to compounds of a particular chemical structure in interchangeable forms and with variations in the displacement of hydrogen atoms and electrons. Thus, two structures can be in equilibrium with the displacement of π electrons and atoms (usually H). For example, enol and ketone Tautomers are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the acid and nitro forms of phenylnitromethane, which are similarly formed by treatment with acid or base. Tautomers can be relevant to achieving optimal chemical reactivity and biological activity of a compound of interest.

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

[0121] Disease, disorder, and condition are used interchangeably herein.

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

[0123] Generally, an "effective amount" of a compound is an amount sufficient to elicit a desired biological response, e.g., a CNS response. It refers to an amount sufficient to treat related disorders, and is sufficient to induce anesthesia or sedation.As understood by those skilled in the art, the effective amount of the compound of the present invention can vary depending on factors such as the desired biological goal, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the age, weight, health status and condition of the subject.An effective amount includes therapeutic treatment and prophylactic treatment.

[0124] As used herein, unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of the disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, an amount that reduces or avoids the symptoms or causes of a disease or condition, or an amount that enhances the therapeutic efficacy of another therapeutic agent.

[0125] As used herein, unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition, or to prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of the disease, disorder, or condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or an amount that enhances the prophylactic efficacy of another prophylactic agent.

[0126] Detailed Description of Specific Embodiments of the Invention Compounds (e.g., compounds of formula (I), compounds of formula (V), or compounds of formula (IX)), pharmaceutical compositions, and methods of use thereof for treating diseases or disorders described herein is provided herein.

[0127] compound The compounds of the present invention as described herein are generally designed to modulate GABA function, thus acting as neurostimulatory steroids for the treatment and prevention of CNS-related conditions in subjects. Modulation, as used herein, refers to the inhibition or potentiation of GABA receptor function. Thus, the compounds and pharmaceutical compositions provided herein find use as therapeutics for the prevention and / or treatment of CNS conditions in mammals, including humans and non-human mammals. Thus, as previously stated, the present invention encompasses and extends within its scope the listed methods of treatment, as well as compounds for such methods and the use of such compounds to prepare medicaments useful for such methods.

[0128] In one aspect, provided herein is a method for treating a pulmonary arthritis, comprising: Formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is [ka] represents a single or double bond, where valence allows; R 2 , R 4 , R 6 , R 11a , and R 11b each independently represents hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, 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 A1where R A1 each instance of is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A1 groups are linked to form a heterocyclic or heteroaryl ring; R A2 is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R 11a and R 11b together to form oxo; R 3 is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; R 5 is absent or is hydrogen; [ka] represents a single or double bond, where [ka] If one of the is a double bond, the other [ka] is a single bond; [ka] If both are single bonds, R 5 is hydrogen; [ka] If one of the groups is a double bond, R 5 does not exist; R 17 is alkoxy, cyano, nitro, aryl, heteroaryl, or -C(O)R B1 , -C(O)CH2R B1, or -C(O)CH2CH2R B1 where R B1 is hydrogen, —OH, alkoxy, aryl, or heteroaryl; R 19 is hydrogen or alkyl; R 7 is halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, 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 or a pharmaceutically acceptable salt thereof.

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

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

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

[0132] In some embodiments, R 2 , R 4 , R 6 , R 11a , and R 11b are all hydrogen. In some embodiments, R 2 , R 4 , and R 6is independently halogen, C1-C6 alkyl, C1-C6 alkoxy, or —OH; in some embodiments, R 3 is C1-C6 alkyl (e.g., C1-C6 haloalkyl or -CH3).

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

[0134] In some embodiments, the compound of formula (I) has formula (II-c) or (II-d): [ka] In some embodiments, R 19 is -CH3. In some embodiments, R 7 is alkyl (e.g., unsubstituted alkyl or -CHOR A1 ) OR -OR A1 In some embodiments, R 7 is —CH, —CHCH, —OH, —OCH, or —CHOCH. In some embodiments, R 17 is —OCH, —CN, or —C(O)CH. 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 is alkoxy, cyano, or -C(O)R B1 In some embodiments, R B1 is pyrazolyl (e.g., cyano-substituted pyrazolyl). In some embodiments, R B1 is tetrazolyl (e.g., methyl-substituted tetrazolyl). In some embodiments, R B1 is a bicyclic heteroaryl (e.g., a methoxy-substituted bicyclic heteroaryl).B1 teeth, [ka] In some embodiments, R B1 teeth, [ka] is.

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

[0136] In some embodiments, R 11a and R 11b is independently hydrogen, C1-C6 alkyl (e.g., C1-C6 haloalkyl), C1-C6 alkoxy (e.g., C1-C6 alkoxyhalo), or —OH. 11a and R 11b taken together form oxo. In some embodiments, R 17 is C1-C6 alkoxy (e.g., —OCH3), cyano, or nitro. 19 is hydrogen or substituted or unsubstituted C1-C6 alkyl (e.g., -CH2OR X , where R X is hydrogen, C1-C6 alkyl, or C1-C6 alkoxy).

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

[0138] In one aspect, provided is a compound of formula (V): [ka] or a pharmaceutically acceptable salt thereof, In formula (V), [ka] represents a single or double bond, where valence allows; R 2 , R 4 , R 6 , R 11a , and R 11b each independently represents hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, 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 where R A1each instance of is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A1 groups are linked to form a heterocyclic or heteroaryl ring; R A2 is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R 11a and R 11b together to form oxo; R 3 is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; R 5 is absent or is hydrogen; [ka] represents a single or double bond, where [ka] If one of the is a double bond, the other [ka] is a single bond; [ka] If both are single bonds, R 5 is hydrogen; [ka] If one of the groups is a double bond, R 5 does not exist; R 17 is alkoxy, cyano, nitro, aryl, heteroaryl, -C(O)R B1 , -C(O)CH2R B1 , or -C(O)CH2CH2R B1 where RB1 is hydrogen, —OH, alkoxy, aryl, or heteroaryl; R 19 is hydrogen or alkyl; R 12 is halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, 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 or a pharmaceutically acceptable salt thereof.

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

[0140] In some embodiments, the compound of formula (V) has formula (Va) or (Vb): [ka] In some embodiments, R 2 , R 4 , R 6 , R 11a , and R 11b Each of R is independently hydrogen. 2 , R 4 , R 6 , R 11a , and R 11b are all hydrogen. In some embodiments, R 2 , R 4 , and R 6 Each of R is independently halogen, C1-C6 alkyl, C1-C6 alkoxy, or —OH. 3 is C1-C6 alkyl (e.g., C1-C6 haloalkyl or -CH3). In some embodiments, the compound of formula (V) has formula (VI-a) or (VI-b): [ka] In some embodiments, the compound of formula (V) is a compound of formula (VI-c) or (VI-d): [ka] In some embodiments, R 19 is -CH3. In some embodiments, R 12 -OR A1 In some embodiments, R 12 is —CH, —CHCH, —OH, —OCH, or —CHOCH. In some embodiments, R 17 is —OCH, —CN, or —C(O)CH. 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 is alkoxy, cyano, or -C(O)R B1 is.

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

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

[0143] In some embodiments, R 11a and R 11b is independently hydrogen, C1-C6 alkyl (e.g., C1-C6 haloalkyl), C1-C6 alkoxy (e.g., C1-C6 haloalkoxy), or —OH. 11a and R 11b taken together form oxo. In some embodiments, R 17 C1 to C6 alkoxy (e.g., —OCH) or cyano. In some embodiments, R 19 is hydrogen or substituted or unsubstituted C1-C6 alkyl (e.g., -CH2OR X , where R X is hydrogen, C1-C6 alkyl, or C1-C6 alkoxy). In some embodiments, the compound of formula (V) is represented by formula (VII-a) or (VII-b): [ka] A compound of the formula In formula (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) has formula (VIII-a) or (VIII-b): [ka] A compound of the formula In formula (VIII-a) or (VIII-b), m is 0, 1, or 2, n is 0, 1, or 2, and R b are each independently hydrogen, halogen, or C1-C6 alkyl; R ceach is independently halogen, C1-C6 alkyl (eg, —CH3 or C1-C6 haloalkyl), C1-C6 alkoxy, cyano, or —OH.

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

[0145] In one aspect, provided herein is a compound of formula (IX): [ka] or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (IX): [ka] represents a single or double bond, where valence allows; R 2 , R 4 , R 6 , R 11a , and R 11b each independently represents hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, 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 where R A1 each instance of is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A1 groups are linked to form a heterocyclic or heteroaryl ring; R A2is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R 11a and R 11b together to form oxo; R 3 is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; R 5 is absent or is hydrogen; [ka] represents a single or double bond, where [ka] If one of the is a double bond, the other [ka] is a single bond; [ka] If both are single bonds, R 5 is hydrogen; [ka] If one of the groups is a double bond, R 5 does not exist; R 17 is alkoxy, cyano, nitro, aryl, heteroaryl, -C(O)R B1 , -C(O)CH2R B1 , or -C(O)CH2CH2R B1 where R B1 is hydrogen, -OH, -N(R A1 )2, alkoxy, aryl, or heteroaryl; R 19 is hydrogen or alkyl; R 16is halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, 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 or a pharmaceutically acceptable salt thereof.

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

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

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

[0149] In some embodiments, R 3 is C1-C6 alkyl (e.g., C1-C6 haloalkyl or -CH3).

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

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

[0152] In some embodiments, R 19 is -CH3. In some embodiments, R 16 is alkyl. In some embodiments, R 16 is —CH, —CHCH, —OH, —OCH, or —CH(CH). In some embodiments, R 17 is —OCH, —CN, or —C(O)CH. 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 is alkoxy, cyano, or -C(O)R B1 In some embodiments, R B1 is pyrazolyl (e.g., cyano-substituted pyrazolyl). In some embodiments, R B1 is tetrazolyl (e.g., methyl-substituted tetrazolyl). In some embodiments, R B1 is a bicyclic heteroaryl (e.g., a methoxy-substituted bicyclic heteroaryl). B1 teeth, [ka] In some embodiments, R B1 teeth, [ka] is.

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

[0154] In some embodiments, R 11a and R 11b each independently represents hydrogen, C1-C6 alkyl In some embodiments, R is alkyl (e.g., C1-C6 haloalkyl), C1-C6 alkoxy (e.g., C1-C6 haloalkoxy), or —OH. 11a and R 11b together to form oxo.

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

[0156] In some embodiments, R 19 is hydrogen or substituted or unsubstituted C1-C6 alkyl (e.g., -CH2OR X , where R X is hydrogen, C1-C6 alkyl, or C1-C6 alkoxy).

[0157] In some embodiments, the compound of formula (IX) has formula (Xa) or (Xb): [ka] A compound of the formula In formula (Xa) or (Xb), R a is hydrogen, halogen, C1-C6 alkyl (e.g., -CH3), or -OH.

[0158] In some embodiments, the compound of formula (IX) has formula (XI-a) or (XI-b): [ka] A compound of the formula In formula (XI-a) or (XI-b), m is 0, 1, or 2, n is 0, 1, or 2, and R b are each independently hydrogen, halogen, or C1-C6 alkyl; R c each is independently halogen, C1-C6 alkyl (eg, —CH3 or C1-C6 haloalkyl), C1-C6 alkoxy, cyano, or —OH.

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

[0160] Also provided herein are the compounds set forth in Table 1 below, or pharmaceutically acceptable salts thereof. do.

[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 contain one or more isotopic substitutions. For example, hydrogen may also be 2 H (D or deuterium) or 3H (T or tritium); carbon can be, for example, 13 C or 14 C; oxygen can be, for example, 18 O; nitrogen can be, for example, 15 N may be In other embodiments, specific isotopes (e.g., 3 H, 13 C. 14 C. 18 O or 15 N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of the element occupying a particular site on the compound.

[0163] Pharmaceutical Compositions In one aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention (also referred to as an "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 can be administered by various routes, including, but not limited to, oral (enteral), parenteral (by injection), rectal, transdermal, intradermal, intrathecal, subcutaneous (SC), intravenous (IV), intramuscular (IM), and intranasal administration.

[0165] Generally, the compounds provided herein are administered in an effective amount. The amount of the compound actually administered is typically determined by a physician in light of the relevant circumstances (including the condition being treated, the selected administration route, the actual compound being administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.).

[0166] When used to prevent the occurrence of CNS disorders, the compounds provided herein can typically be administered to subjects at risk of developing the condition at the dosage levels described above, under the advice and supervision of a physician. Subjects at risk of developing a particular condition generally include subjects with a family history of the condition, or subjects identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0167] The pharmaceutical compositions provided herein may also be administered chronically ("chronic administration"). Chronic administration refers to administration of a compound or pharmaceutical composition thereof that can be continued for an extended period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or indefinitely, e.g., for the remainder of the subject's life. In certain embodiments, chronic administration is intended to provide a constant level of the compound in the blood, e.g., within the therapeutic window, for an extended period of time.

[0168] The pharmaceutical composition of the present invention can also be delivered using various dosing methods.For example, in certain embodiments, the pharmaceutical composition can be given as a bolus, for example, to raise the concentration of the compound in the blood to an effective level.The placement of the bolus dose depends on the systemic level of the active ingredient desired throughout the body; for example, an intramuscular or subcutaneous bolus dose allows for a slow release of the active ingredient, while a bolus delivered directly into a vein (for example, by IV infusion) allows for a faster delivery, which quickly raises the concentration of the active ingredient in the blood to an effective level.In other embodiments, the pharmaceutical composition can 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 still other embodiments, the pharmaceutical composition can be initially administered as a bolus dose, followed by continuous infusion.

[0169] Compositions for oral administration can take the form of bulk liquid solutions or suspensions or bulk powders. However, more commonly, compositions are provided in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unit dosages for human subjects and other mammals, each unit containing a predetermined amount of active ingredient calculated to produce a desired therapeutic effect, together with suitable pharmaceutical excipients. Typical unit dosage forms include pre-measured, pre-filled ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc., for solid compositions. In such compositions, the compound is usually a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various vehicles or excipients and processing aids useful in forming the desired dosage form.

[0170] For oral administration, a typical regimen is 1 to 5 times, particularly 2 to 4 times, and typically 3 times per day. Using these dosing patterns, each dose provides about 0.01 to about 20 mg / kg of a compound provided herein, with preferred doses being about 0.1 to about 10 mg / kg, particularly about 1 to about 5 mg / kg.

[0171] Transdermal doses are generally selected to provide blood levels similar to or lower than those achieved using injection doses, and generally range from about 0.01% to about 20% by weight, preferably from about 0.1% to about 20% by weight, preferably from about 0.1% to about 10% by weight, and more preferably from about 0.5% to about 15% by weight.

[0172] Injectable dose levels range from about 0.1 mg / kg / hour to at least 20 mg / kg / hour, all over a period of about 1 to about 120 hours, particularly 24 to 96 hours. A preloading bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady-state levels. The maximum total dose is not expected to exceed about 5 g / day for a 40-80 kg human patient.

[0173] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors, etc. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: binders (e.g., microcrystalline cellulose, gum tragacanth, or gelatin); excipients (e.g., starch or lactose); disintegrating agents (e.g., alginic acid, Primogel, or corn starch); lubricants (e.g., magnesium stearate); glidants (e.g., colloidal silicon dioxide); sweetening agents (e.g., sucrose or saccharin); or flavoring agents (e.g., peppermint, methyl salicylate, or orange flavor).

[0174] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline or other injectable excipients known in the art. Conventionally, the active compound in such compositions is typically a minor component, often about 0.05-10% by weight, with the remainder being the injectable excipient, etc.

[0175] Transdermal compositions are typically formulated as topical ointments or creams containing active ingredient(s).When formulated as an ointment, active ingredient is typically mixed with a paraffin ointment base or a water-miscible ointment base.Alternatively, active ingredient can 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 additional ingredients that enhance the skin penetration or stability of active ingredient or formulation.All such known transdermal formulations and ingredients are included within the scope provided herein.

[0176] The compounds provided herein can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type or of a solid matrix variety.

[0177] The components described above for orally administrable, injectable, or topically administrable compositions are merely representative. Other materials, processing techniques, and the like are set forth in Part 8 of Remington's Pharmaceutical Sciences, 17th Edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0178] The compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[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 pharmacologically acceptable anions (e.g., hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, etc.).

[0180] In another aspect, the present invention provides pharmaceutical compositions (eg, compositions suitable for injection, such as intravenous (IV) administration) comprising a compound of the present invention and a pharmaceutically acceptable excipient.

[0181] Pharmaceutically acceptable excipients include any and all diluents or other liquid vehicles suitable for the particular dosage form desired, e.g., injection, dispersing or suspending aids, surfactants, isotonic agents, preservatives, lubricants, etc. General considerations in 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, injectable preparations, such as sterile injectable aqueous suspensions, can be formulated by known techniques using suitable dispersing or wetting agents and suspending agents. Exemplary excipients that can 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, which consist of six, seven, and eight 1,4-linked glucose units, respectively, optionally containing one or more substituents 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 a sulfoalkyl ether β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, also known as Captisol®. See, e.g., 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] Injectable compositions can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0185] Generally, the compounds provided herein are administered in an effective amount. The amount of the compound actually administered is typically determined by a physician in light of the relevant circumstances (including the condition being treated, the selected administration route, the actual compound being administered, the age, weight, response, and severity of the patient's symptoms, etc.).

[0186] The compositions are provided in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined amount of active ingredient calculated to produce a desired therapeutic effect, together with suitable pharmaceutical excipients. Typical unit dosage forms include pre-measured, pre-filled ampoules or syringes of liquid compositions. In such compositions, the compound is usually a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various vehicles or carriers and processing aids useful for forming the desired dosage form.

[0187] The compounds provided herein can be administered as a single active agent or can be administered in combination with other active agents.In one aspect, the present invention provides a combination of the compounds of the present invention with another pharmacologically active agent.The administration of the combination can be carried out by any technique that is clear to those skilled in the art, including, for example, separate administration, sequential administration, simultaneous administration and alternating administration.

[0188] Although the description of pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, those skilled in the art will understand that such compositions are generally suitable for administration to animals of all kinds. Modifications of pharmaceutical compositions suitable for administration to humans to make them suitable for administration to a variety of animals are well understood, and a veterinary pharmacologist of ordinary skill can design and / or perform such modifications with routine experimentation. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy, 1999, 144:145-146, 1999, 1999, 1999, 1999, 2000, 2001, 2002, 2003, 2004, 2005, 2006, 2007, 2008, 2009, 2010, 2011, 2012, 2013, 2014, 2015, 2016, 2017, 2018, 2019, 2020, 2021, 2022, 2023, 2024, 2025, 2026, 2027, 2028, 2030, 2030, 2031, 2032, 2033, 2034, 2035, 2036, 2037, 2040, 2041, 2042, 2043, 2044, 2045, 2046, 2047, 2048, 2049, 2050, 2051, 2052, 2053, 2054, 2055, 2056, 2057, 206 21st ed., Lippincott Williams & Wilkins, 2005.

[0189] Methods of Use and Treatment In yet another aspect, there is provided a method of reducing or preventing seizure activity in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention. In some embodiments, the method reduces or prevents epileptogenesis.

[0190] In some embodiments, it is contemplated that such compounds are useful as therapeutic agents for treating a CNS-related disorder (e.g., a sleep disorder, a mood disorder (e.g., depression), a schizophrenia spectrum disorder, a seizure disorder, epileptogenesis, a disorder of memory and / or cognition, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, or tinnitus) in a subject in need thereof (e.g., a subject 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., minor depression), bipolar disorder (e.g., type I and / or type II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder (SAD), and others]. anxiety disorder), stress, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (e.g., obsessive-compulsive disorder (OCD)), schizophrenia spectrum disorder (e.g., schizophrenia, schizoaffective disorder), seizure disorder (e.g., epilepsy (e.g., status epilepticus (SE)), seizures), memory and / or cognitive impairment (e.g., attention disorder (e.g., attention deficit hyperactivity disorder (ADHD)), dementia (e.g., Alzheimer's disease, Lewis body type dementia, dementia, vascular dementia], movement disorders (e.g., Huntington's disease, Parkinson's disease), personality disorders (e.g., antisocial personality disorder, obsessive-compulsive personality disorder), autism spectrum disorders (ASD) (e.g., autism, a host of causes of autism such as synaptophathy (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 disease (e.g., stroke, ischemia, vascular malformation), substance abuse disorders and / or withdrawal syndromes (e.g., opiate, cocaine, and / or alcohol addiction), and tinnitus.

[0191] In yet another aspect, the present invention provides a combination of the compound of the present invention with another pharmacologically active agent.The compound provided herein can be administered as a single active agent or can be administered in combination with other agents.The administration of the combination can proceed by any technique that is clear to those skilled in the art, including, for example, separate administration, sequential administration, simultaneous administration, and alternating administration.

[0192] In another aspect, there is provided a method of treating or preventing brain excitation in a subject susceptible to or afflicted with a condition associated with brain excitation, comprising administering to the subject an effective amount of a compound of the invention.

[0193] In yet another aspect, there is provided a method of treating or preventing stress or anxiety in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention or a composition thereof.

[0194] In yet another aspect, there is provided a method of alleviating or preventing insomnia in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention or a composition thereof.

[0195] In yet another aspect, there is provided a method for inducing sleep and substantially maintaining the level of REM sleep seen in normal sleep, without inducing substantial rebound insomnia, comprising administering an effective amount of a compound of the invention.

[0196] In yet another aspect, there is provided a method of alleviating or preventing PMS or PND in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention.

[0197] In yet another aspect, there is provided a method of treating or preventing a mood disorder in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention. In certain embodiments, the mood disorder is depression.

[0198] In yet another aspect, a method for treating cognitive enhancement or memory impairment is provided 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] In yet another aspect, by administering to a subject a therapeutically effective amount of a compound of the invention In certain embodiments, a method for treating an attention disorder is provided. In certain embodiments, the 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 dysfunction Methods that can be used to treat neuroendocrine disorders and dysfunctions are provided herein. As used herein, "neuroendocrine disorder" or "neuroendocrine dysfunction" refers to various conditions caused by an imbalance in the body's hormone production, which is directly related to the brain. Neuroendocrine disorders involve interactions between the nervous system and the endocrine system. The hypothalamus and pituitary gland are two areas of the brain that control hormone production, so 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). In some embodiments, women's health disorders or conditions are associated with A related neuroendocrine disorder or dysfunction is polycystic ovary syndrome.

[0202] Symptoms of neuroendocrine disorders include, but are not limited to, behavioral, emotional, and sleep-related symptoms, symptoms related to reproductive function, and physical symptoms, including, but not limited to, fatigue, poor memory, anxiety, depression, weight gain or loss, emotional lability, lack of concentration, difficulty paying attention, loss of lipids, infertility, amenorrhea, loss of muscle mass, increased abdominal body fat, low blood pressure, low heart rate, hair loss, anemia, constipation, cold intolerance, and dry skin.

[0203] Neurodegenerative Diseases and Disorders Provided herein are methods that can be used to treat neurodegenerative diseases and disorders. The term "neurodegenerative disease" includes diseases and disorders associated with the progressive loss of neuronal structure or function, or the death of neurons. Neurodegenerative diseases and disorders include Alzheimer's disease (including associated symptoms of mild, moderate, or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic injury; ataxia and convulsions (including for the treatment and prevention, and for the prevention of seizures caused by schizoaffective disorder or by drugs used to treat schizophrenia); benign amnesia; cerebral edema; cerebellar ataxia (including McLeod neuroacanthocytosis syndrome (MLS)); closed head injury; coma; contusion injury (e.g., spinal cord injury and head injury); dementia (including multi-infarct dementia and senile dementia); disorders of consciousness; Down's syndrome; drug-induced or pharmaceutical-induced akathisia (e.g., neuroleptic-induced acute akathisia, acute ataxia, tremor paralysis, or tardive dyskinesia, neuroleptic malignant syndrome, or drug-induced postural tremor); epilepsy; fragile X syndrome; Gilles de la Tourette syndrome; head trauma; hearing impairment and hearing loss; Huntington's disease; Lennox syndrome; levodopa-induced dyskinesia; mental retardation; movement disorders including akinesia and akinesia (rigidity) syndrome (brainstem neurocalcification, corticobasal degeneration, multiple system atrophy, tremor tremor-ALS dementia complex, Parkinson's disease, postencephalitic tremor tremor and progressive tremor tremor) supranuclear palsy; muscle spasticity and disorders associated with muscle spasticity or weakness (chorea (e.g., benign hereditary chorea, drug-induced chorea, hemiballismus, Huntington's disease, neuroacanthocytosis, Sydenham's chorea, and symptomatic chorea), dyskinesia (including tics such as complex tics, simple tics, and symptomatic tics), myoclonus (including generalized myoclonus and focal cyloclonus), tremor (e.g., resting tremor, postural tremor, and intention tremor), and Neuronal damage (including ocular damage, ocular retinopathy or macular degeneration); neurotoxic disorders following stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest; Parkinson's disease; seizures; status epilepticus; stroke; tinnitus; renal tubular sclerosis, and neurodegeneration induced by viral infections (such as those caused by acquired immune deficiency syndrome (AIDS) and encephalopathy). 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 neurotoxicity 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 disorders Also provided herein are methods for treating mood disorders, such as clinical depression, postpartum depression or postpartum depression, perinatal depression, atypical depression, melancholic depression, psychogenic major depression, catatonic depression, seasonal affective disorder, dysthymia, dual depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar disorder or manic-depressive disorder, depression caused by a chronic medical condition, treatment-resistant depression, refractory depression, suicide, suicidal ideation, or suicidal behavior. In some embodiments, the methods described herein provide a therapeutic effect for subjects suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is associated with a disease or disorder described herein (e.g., neuroendocrine diseases and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), movement disorders, tremors (e.g., Parkinson's disease), women's health disorders or conditions).

[0205] Clinical depression, also known as major depression, major depressive disorder (MDD), unipolar depression, unipolar disorder, and recurrent depression, refers to a mental disorder characterized by a pervasive and persistent low mood accompanied by low self-esteem and a loss of interest or pleasure in normally enjoyable activities. Some people with clinical depression have difficulty sleeping, become thin, and generally feel agitated and irritable. Clinical depression affects how individuals feel, think, and behave, and can lead to a variety of emotional and physical problems. Individuals with clinical depression may have difficulty performing daily activities and may feel as if life is not worth living.

[0206] Perinatal depression refers to depression during pregnancy. Symptoms include irritability, crying, agitation, difficulty sleeping, extreme fatigue (emotional and / or physical), changes in appetite, difficulty concentrating, increased anxiety and / or worry, feelings of separation from the infant and / or fetus, and loss of interest in previously enjoyable activities.

[0207] Postpartum depression (PND), also known as postpartum depression (PPD), refers to a type of clinical depression that women suffer from after giving birth.Symptoms may include sadness, fatigue, changes in sleep and eating habits, decreased sexual desire, crying episodes, anxiety and irritability.In some embodiments, PND is treatment-resistant depression (for example, treatment-resistant depression as described herein).In some embodiments, PND is treatment-refractory depression (for example, treatment-refractory depression as described herein).

[0208] In some embodiments, the subject with PND also experiences depression or symptoms of depression during pregnancy.This depression is referred to herein as perinatal depression.In some embodiments, the subject experiencing perinatal depression has a high risk of experiencing PND. .

[0209] Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anhedonia) and aggressiveness, significant weight gain, or increased appetite. Patients with AD may also have significant social impairment as a result of excessive sleep or somnolence (hypersomnia), a feeling of heaviness in the limbs, and hypersensitivity to perceived interpersonal rejection.

[0210] Melancholic depression is characterized by loss of pleasure in most or all activities (anhedonia), unresponsiveness to pleasurable stimuli, a depressed mood that is more pronounced than a mood of sadness or loss, excessive weight loss, or excessive feelings of guilt.

[0211] Psychotic major depression (PMD) or psychotic depression refers to a major depressive episode, particularly one of a melancholic nature, in which an individual experiences psychotic symptoms such as delusions and hallucinations.

[0212] Catatonic depression refers to major depression accompanied by disturbances in motor behavior and other symptoms. Individuals may become mute and stuporous, become immobile, or exhibit aimless or bizarre movements.

[0213] Seasonal affective disorder (SAD) refers to a type of seasonal depression in which an individual has a seasonal pattern of depressive episodes that begin occurring in the fall or winter.

[0214] Dysthymia refers to a condition related to unipolar depression in which the same physical and cognitive problems are evident, although they tend to be less severe and last longer (e.g., at least 2 years).

[0215] Dual depression refers to a severely depressed mood (dysthymia) lasting at least two years and interrupted by periods of major depression.

[0216] Depressive personality disorder (DPD) refers to a personality disorder with depressive features.

[0217] Recurrent Brief Depression (RBD) refers to a condition in which an individual has depressive episodes approximately once per month, with each episode lasting two weeks or less, typically less than two to three days.

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

[0219] Bipolar disorder or manic-depressive disorder causes extreme mood swings, including high affect (mania or hypomania) and low affect (depression). During manic periods, individuals may feel or act unusually happy, energetic, or irritable. They often make thoughtless decisions with little regard for consequences. They usually have a decreased need for sleep. During depressive periods, individuals may cry uncontrollably, make less eye contact with others, and have a negative outlook on life. The risk of suicide for people with this disorder is high—more than 6% over a 20-year period—and 30–40% will engage in self-harm. Other mental health problems, such as anxiety disorders and substance use disorders, commonly coexist with bipolar disorder.

[0220] Chronic condition-induced depression refers to depression caused by a chronic medical condition such as cancer or chronic pain, chemotherapy, or chronic stress.

[0221] Treatment-resistant depression refers to the state that individuals are treated for depression but their symptoms do not improve.For example, antidepressants or psychological counseling (psychotherapy) do not alleviate the depressive symptoms of individuals with treatment-resistant depression.In some cases, individuals with treatment-resistant depression improve their symptoms, but then return.Treatment-resistant depression occurs in patients with depression that is resistant to standard pharmacological treatments, including tricyclic antidepressants, MAOIs, SSRIs, and double and triple uptake inhibitors, and / or anxiolytics, and non-pharmacological treatments (for example, psychotherapy, electroconvulsive therapy, vagus nerve stimulation and / or transcranial magnetic stimulation).

[0222] Postoperative depression refers to a state of depression following a surgical procedure (e.g., as a result of facing death). For example, an individual may experience persistent feelings of sadness or emptiness, loss of pleasure or interest in hobbies and activities that they normally enjoy, or persistent feelings of worthlessness or hopelessness.

[0223] A mood disorder associated with a women's health condition or disorder refers to a mood disorder (e.g., depression) that is associated with (e.g., caused by) a women's health condition or disorder (e.g., those described herein).

[0224] Suicidal tendencies, ideation, and behavior refer to an individual's tendency to commit suicide. Suicidal ideation involves thoughts about or an abnormal obsession with suicide. The spectrum of suicidal ideation varies widely, from fleeting thoughts to extensive thinking, detailed plans, role-playing, and abortive attempts. Symptoms may include talking about suicide, obtaining the means to commit suicide, withdrawing from social contacts, preoccupation with death, feeling trapped or hopeless about a situation, increased alcohol or drug use, engaging in risky or self-destructive behavior, and saying goodbye to people as if they will never see each other again.

[0225] Symptoms of depression include persistent anxious or sad feelings, helpless feelings, hopelessness, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, motor challenges, loss of interest in pleasurable activities or hobbies, poor concentration, low energy, low self-esteem, lack of positive thoughts or plans, excessive sleep, overeating, loss of appetite, insomnia, self-harm, thoughts of suicide and suicide attempts.The presence, severity, frequency and duration of symptoms may vary from case to case.Depression symptoms and their alleviation can be confirmed by a doctor or psychologist (for example, mental status examination).

[0226] In some embodiments, the method provides a therapeutic effect (e.g., as 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 in the HAM-D score from baseline at the end of the treatment period (e.g., 12 hours, 24 hours, 48 ​​hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, or more after administration). In some embodiments, the decrease in the HAM-D score from baseline is from severe (e.g., a HAM-D score of 24 or more) to asymptomatic (e.g., a HAM-D score of 7 or less). In some embodiments, the baseline score is about 10 to 52 (e.g., greater than 10, greater than 15, or greater than 20; 10 to 52, 12 to 52, 15 to 52, 17 to 52, 20 to 52, 22 to 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 about 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 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 about 20-30 (e.g., 22-28, 23-27, 24-27, 25-27, 26-27) to a HAM-D score of about 0-10 (e.g., less than 10; 0-10, 0-6, 0-4, 0-3, 0-2, 1.8) at the end of the treatment period. In some embodiments, the reduction in 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-fold. In some embodiments, the reduction in 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 from baseline in the HAM-D score at the end of the treatment period (e.g., 12 hours, 24 hours, 48 ​​hours; 24 hours, 48 ​​hours, 72 hours, 96 hours or more after administration) of at least 10 points, 15 points, or 20 points. In some embodiments, the therapeutic effect is a reduction from baseline in the HAM-D score at the end of the treatment period (e.g., 12 hours, 24 hours, 48 ​​hours; 24 hours, 48 ​​hours, 72 hours, 96 hours or more after administration) of at least 5 points, 7 points, or 10 points greater than the therapeutic effect achieved by placebo treatment.

[0227] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a decrease 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 (related to outward sadness, verbal sadness, internal tension, decreased sleep, decreased appetite, difficulty concentrating, fatigue, inability to hold emotions, pessimistic thoughts, and suicidal thoughts) used by psychiatrists to measure the severity of depressive episodes in patients with mood disorders. A score of 0-6 indicates normal / no symptoms; a score of 7-19 indicates mild depression; a score of 20-34 indicates moderate depression; and a score of more than 34 indicates severe depression. In some embodiments, the therapeutic effect is a reduction in the MADRS score from baseline at the end of the treatment period (e.g., 12 hours, 24 hours, 48 ​​hours; 24 hours, 48 ​​hours, 60 hours, 72 hours, 96 hours, or more after administration). In some embodiments, the reduction in the MADRS score from baseline ranges from severe (e.g., a MADRS score of 30 or more) to asymptomatic (e.g., a MADRS score of 20 or less). For example, the mean change from baseline in the total MADRS score resulting from treatment with a compound described herein is about -15, -20, -25, -30, while the mean change from baseline in the total MADRS score resulting from treatment with a placebo is about -15, -10, -5.

[0228] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a reduction 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., as measured by a reduction in the Clinical Global Impression (CGI) score) 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 a therapeutic effect (e.g., as measured by a reduction in the Generalized Anxiety Disorder 7-item scale (GAD-7)) within 4 days, within 3 days, within 2 days, within 1 day; 24 hours, 20 hours, 16 hours, 12 hours, 10 hours, 8 hours, or less.

[0231] Anxiety disorders 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 an umbrella term that encompasses several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders.

[0232] Generalized anxiety disorder (GAD) is a common chronic disorder characterized by long-term anxiety that cannot be focused on any one object or situation. People suffering from GAD experience persistent, nonspecific fear and worry and become excessively worried about mundane events. GAD is the most common anxiety disorder affecting older adults.

[0233] In panic disorder, people suffer from brief attacks of intense fear and anxiety, often characterized by trembling, shaking, confusion, dizziness, nausea, and difficulty breathing. These panic attacks (defined by the APA as sudden onset of fear or discomfort that peaks in less than 10 minutes) can last for hours and can be triggered by stress, fear, or even exercise, although a specific cause is not always apparent. In addition to recurrent and unpredictable panic attacks, a diagnosis of phobic disorder also requires that the attacks have chronic consequences (either worry about the attack's potential meaning, persistent fear of future attacks, or significant changes in behavior related to the attack). Thus, patients with phobic disorder experience symptoms even outside of a specific panic episode. Often, normal changes in heart rate are noticed by the panic sufferer, leading them to believe that something is wrong with their heart or that they are experiencing another panic attack. In some cases, a heightened perception of bodily functions (hypervigilance) occurs during a panic attack, in which any perceived physiological change is interpreted as a possible life-threatening illness (i.e., excessive hypochondria).

[0234] Obsessive-compulsive disorder (OCD) is a type of anxiety disorder primarily characterized by recurrent obsessions (distressing, persistent, intrusive thoughts or images) and compulsions (urges to perform specific actions or rituals). OCD thought patterns can be linked to superstition, insofar as they involve the individual believing in nonexistent causal relationships. Often, the process is completely illogical. For example, a compulsion to walk in a particular pattern can be used to alleviate obsessive thoughts of impending danger. And in many cases, the compulsion is not entirely inexplicable but is simply a nervously triggered urge to complete a ritual. In a minority of cases, OCD patients may only experience obsessions without overt compulsions, and even fewer experience only compulsions.

[0235] One of the largest categories of anxiety disorders is that of phobias, which encompasses all cases in which fear and anxiety are triggered by a particular stimulus or situation. Patients typically anticipate frightening consequences from encountering the object of their fear (which could be anything from an animal to a place to a bodily fluid).

[0236] Post-traumatic stress disorder, or PTSD, is an anxiety disorder that results from a traumatic experience. Post-traumatic stress can result from extreme situations (e.g., war, rape, hostage situations, or even serious misfortune). It can also result from prolonged (chronic) exposure to severe stressors (e.g., soldiers who tolerate individual combat but do not cope well with continuous war). Common symptoms include flashbacks, avoidance behaviors, and depression.

[0237] Women's health problems Provided herein is a method for treating conditions or disorders related to women's health.Conditions or disorders related to women's health include but are not limited to gynecological health and disorders (for example, premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD)), pregnancy problems (for example, miscarriage, abortion), infertility and related disorders (for example, polycystic ovary syndrome (PCOS)), other disorders and conditions, and problems related to women's overall health and well-being (for example, menopause).

[0238] Gynecological health and disorders affecting women include menstruation and menstrual irregularities; urinary tract health (including urinary incontinence and pelvic floor disorders); and disorders such as bacterial vaginosis, vaginitis, uterine fibroids, and vulvodynia.

[0239] Premenstrual syndrome (PMS) refers to physical and emotional symptoms that occur one to two weeks before menstruation. Symptoms vary but can include bleeding, mood swings, breast tenderness, bulimia, fatigue, irritability, acne, and depression.

[0240] Premenstrual dysphoric disorder (PMDD) is a severe form of PMS. Symptoms of PMDD are similar to 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, appetite changes, feelings of loss of control or confusion, sleep problems, and physical problems (e.g., bloating, breast tenderness, swelling, headaches, joint or muscle pain).

[0241] Pregnancy issues include preconception and prenatal care, pregnancy loss (miscarriage and stillbirth), preterm labor and birth, sudden infant death syndrome (SIDS), breastfeeding, and birth defects.

[0242] 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 occur up to 28 weeks into pregnancy.

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

[0245] Polycystic ovary syndrome (PCOS) refers to an endocrine system disorder in women of reproductive age. PCOS is a group 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 menstrual periods, heavy periods, excess body and facial hair, acne, pelvic pain, difficulty conceiving, and patches of thickened, dark, smooth skin. PCOS can be associated with conditions including 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 disabilities and unique challenges, osteoporosis and bone health, and menopause.

[0248] Menopause refers to the 12 months after a woman's last menstrual period and marks the end of the menstrual cycle. Menopause typically occurs in women in their 40s or 50s. Physical symptoms of menopause, such as hot flashes and emotional symptoms, can interfere with sleep, reduce energy, cause anxiety or sadness, or Menopause can cause a sense of loss. Menopause includes natural menopause and surgical menopause (which is induced menopause due to events such as surgery (e.g., hysterectomy, oophorectomy; cancer)). Menopause is induced when the ovaries are severely damaged, for example, by radiation, chemotherapy, or other medications.

[0249] epilepsy A compound of formula (I), a compound of formula (V), or a compound of formula (IX), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof, can be used in the methods described herein, for example, as described in WO2013 / 112605 and WO / 2014 / 031792, the contents of which are incorporated herein in their entireties, for example, to treat a disorder described herein, such as epilepsy, status epilepticus, or seizures.

[0250] Epilepsy is a brain disorder characterized by repeated seizures over a long period of time. Types of epilepsy can include, but are not limited to, generalized epilepsy, such as childhood absence epilepsy, juvenile myoclonic epilepsy, epilepsy with awakening grand mal seizures, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, such as temporal lobe epilepsy, frontal lobe epilepsy, and benign focal epilepsy of childhood.

[0251] Epilepsy The compounds and methods described herein can be used to treat or prevent epileptogenesis.Epileptogenesis is a step-by-step process in which a normal brain develops epilepsy (a chronic condition in which seizures occur).Epileptogenesis results from neuronal damage caused by an initial injury (for example, 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 very refractory status epilepticus; non-convulsive status epilepticus, such as generalized status epilepticus, complex partial status epilepticus, generalized periodic epileptic discharges, and periodic unilateral epileptic discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epilepticus and can include early status epilepticus, established status epilepticus, refractory status epilepticus, and very refractory status epilepticus. Early status epilepticus is treated with first-line therapy. Established status epilepticus is characterized by persistent status epilepticus despite treatment with first-line therapy and second-line therapy is administered. Refractory status epilepticus is characterized by persistent status epilepticus despite treatment with first-line and second-line therapy and general anesthetics are commonly administered. Super-refractory status epilepticus is characterized by persistent status epilepticus despite treatment with first-line therapy, second-line therapy, and general anesthetics for 24 hours or more.

[0253] Non-convulsive status epilepticus can include, for example, focal non-convulsive status epilepticus, e.g., complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, minimal non-convulsive status epilepticus; generalized non-convulsive status epilepticus, e.g., late-onset absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus.

[0254] The compounds of formula (I), formula (V), or formula (IX), or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable compositions thereof, may also be used to treat CNS disorders, such as traumatic brain injury, status epilepticus, e.g., convulsive seizures, prior to the onset of a seizure. It can be administered as prophylaxis to subjects with status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, very refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptic discharges; and periodic unilateral epileptic discharges.

[0255] Seizures A seizure is a physical finding or change in behavior that occurs after an episode of abnormal electrical activity in the brain. The term "seizure" is often used interchangeably with "convulsion." A convulsion is when a person's body shakes rapidly and uncontrollably. During a convulsion, the person's muscles repeatedly contract and relax.

[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 the type of seizure helps doctors diagnose whether 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 in a smaller part of the brain. The part of the brain that generates the seizure is sometimes called the focus.

[0258] There are six types of generalized seizures. The most common, dramatic, and therefore best known is a generalized convulsion (also called a grand mal seizure). In this type of seizure, the patient loses consciousness and usually collapses. This loss of consciousness is followed by 30-60 seconds of generalized rigidity (called the "tonic" phase of the seizure), followed by 30-60 seconds of violent spasms (the "clonic" phase), after which the patient falls into a deep sleep (the "postictal" or after-seizure phase). During a grand mal seizure, impairments and accidents (e.g., tongue biting and urinary incontinence) can occur.

[0259] Absence attacks cause a brief (only a few seconds) loss of consciousness with few or no symptoms. Patients (most often children) typically stop activity and stare blankly. These attacks begin and end abruptly and can occur several times a day. Patients are usually unaware they are having a attack, except that they may notice they are "losing time."

[0260] Myoclonic seizures consist of sporadic jerks, usually on both sides of the body. Patients sometimes describe these jerks as brief electric shocks. When severe, these seizures can result in dropping or involuntary throwing of objects.

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

[0262] Tonic seizures are characterized by muscle stiffness.

[0263] Atonic seizures consist of a sudden loss of muscle tone throughout the body, especially the arms and legs, often resulting in a fall.

[0264] Seizures as described herein include epileptic seizures; acute repetitive seizures; cluster seizures; continuous seizures; continuous seizures; persistent seizures; recurrent seizures; status epilepticus, e.g., refractory convulsive status epilepticus, non-convulsive status epilepticus; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondarily generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign rolandic seizures; febrile seizures; affective seizures; focal The seizures may include: seizures; gales; generalized onset seizures; infantile spasms; Jacksonian seizures; generalized bilateral myoclonic seizures; multifocal seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post-traumatic seizures; petit mal seizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures. In some embodiments, the seizures are generalized seizures associated with Dravet syndrome, Lennox-Gastaut syndrome, tuberous sclerosis complex, Rett syndrome, or PCDH19 female epilepsy.

[0265] Movement disorders Also described herein is the method for treating movement disorders.As used herein, " movement disorders " refers to various diseases and disorders related to hyperkinesia and related abnormalities in muscle control.Exemplary movement disorders include but are not limited to Parkinson's disease and paralysis (particularly defined by bradykinesia), dystonia, chorea and Huntington's disease, ataxia, tremor (for example, essential tremor), myoclonus and startle, tic and Tourette's syndrome, restless leg syndrome, stiff person syndrome and gait disorder.

[0266] shaking The methods described herein can be used to treat tremor, for example, the compounds of Formula (I) can be used to treat, for example, cerebellar or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, Parkinson's tremor, physiological tremor, psychogenic tremor, or rubral tremor. Tremor includes genetic, degenerative, and idiopathic disorders, such as Wilson's disease, Parkinson's disease, and essential tremor, respectively; metabolic diseases (e.g., thyroid-parathyroid disease, liver disease, and hypoglycemia); peripheral neuropathies (associated with Charcot-Marie-Tooth disease, Lucy-Lewy disease, diabetes mellitus, and complex regional pain syndrome); disorders induced by toxins (nicotine, mercury, lead, CO, manganese, arsenic, toluene); disorders induced by drugs (hypnotics, tricyclics, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremor can be classified as physiologic tremor, fatigue-induced enhanced physiologic tremor, essential tremor syndromes (including classic essential tremor, primary orthostatic tremor, and task- and postural-specific tremor), dystonic tremor, Parkinsonian tremor, cerebellar tremor, Holmes' tremor (i.e., red nucleus tremor), palatal tremor, neuropathic tremor, toxic or drug-induced tremor, and psychogenic tremor.

[0267] Tremor is an involuntary, sometimes rhythmic, contraction and relaxation of muscles that may involve vibration or spasm of one or more body parts (e.g., hands, arms, eyes, face, head, vocal cords, trunk, legs).

[0268] Cerebellar tremor, or intention tremor, is a slow, widespread tremor of the limbs that occurs after a purposeful movement. Cerebellar tremor is caused by lesions in or damage to the cerebellum, for example, due to tumors, stroke, or disease (e.g., multiple sclerosis, inherited degenerative disorders).

[0269] Dystonic tremor occurs in individuals suffering from dystonia, a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive movements and / or painful abnormal postures or positions. Dystonic tremor can affect any muscle in the body. Dystonic tremor occurs irregularly and can often be relieved by complete rest.

[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 spreading to both sides within three years. Tremors can be slow and progressive, affecting all parts of the body. The hands are most frequently affected, but the head, voice, tongue, legs, and trunk can also be involved. Tremor frequency can decrease with age, but severity can increase. Emotional excitement, stress, fever, physical fatigue, or hypoglycemia can trigger tremors and / or increase their severity. Symptoms generally develop over a long period of time and can become visible and persist after onset.

[0271] Orthostatic tremor is characterized by rapid (e.g., greater than 12 Hz) rhythmic muscle contractions in the legs and trunk immediately after standing. Spasms are felt in the thighs and legs, and patients may tremble uncontrollably when asked to stand in one position. Orthostatic tremor can occur in patients with essential tremor.

[0272] Parkinsonian tremor is caused by damage to structures in the brain that control movement. Parkinsonian tremor is often a precursor to Parkinson's disease and is typically seen as a "pill-rolling" movement of the hand, and can also affect the chin, lips, legs, and trunk. The onset of Parkinsonian tremor typically begins after age 60. Movements may begin in one limb or one side of the body and progress to the other side.

[0273] Physiologic tremor can occur in normal individuals and has no clinical significance. Physiologic tremor can be seen in all voluntary muscle groups. Physiologic tremor can be caused by certain drugs, alcohol withdrawal, or medical conditions including hyperthyroidism and hypoglycemia. This tremor classically has a frequency of approximately 10 Hz.

[0274] Psychogenic or hysterical tremor can occur at rest or during postural or active movement. Patients with psychogenic tremor may have conversion disorder or another psychiatric illness.

[0275] Red nucleus tremor is characterized by slow, coarse tremors that can be present at rest, during posture, and with intention. This tremor may be related to conditions affecting the red nucleus in the classical and rare strokes of the midbrain.

[0276] Parkinson's disease affects the nerve cells in the brain that produce dopamine. Symptoms include muscle rigidity, tremor, and changes in speech and gait. Paresis tremens is characterized by tremor, bradykinesia, rigidity, and postural instability. Paresis tremens shares symptoms with Parkinson's disease, but is a group of conditions rather than a progressive neurodegenerative disease.

[0277] Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions that cause abnormal, often repetitive movements or postures. Dystonic movements can be patterned, twisting, or tremulous. Dystonia is often precipitated or exacerbated by voluntary movements and is often associated with overflow of muscle activation.

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

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

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

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

[0282] Tics are involuntary movements that usually occur suddenly, are short, repetitive, but not rhythmic, and typically mimic normal behaviors and often occur outside the background of normal activity. Tics can be classified as motor or vocal, with motor tics associated with movement and vocal tics associated with sound. Tics can be characterized as simple or complex. For example, simple motor tics involve only a few muscles confined to a specific body part. Tourette's syndrome is a childhood-onset, inherited neuropsychiatric disorder characterized by multiple motor tics and at least one vocal tic.

[0283] Restless legs 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 movement disorder characterized by involuntary, painful spasms and muscle stiffness, usually involving the lower back and legs. It typically presents with a stiff gait accompanied by excessive lumbar hyperlordosis. It typically presents with characteristic abnormalities in EMG recordings of continuous motor unit activity of paraspinal axial muscles. Variants include "stiff-limb syndrome," which typically affects the distal legs and feet, resulting in focal stiffness.

[0285] Gait disorders refer to abnormalities in the manner or style of walking resulting from neuromuscular, arthritic, or other physical changes. Gaits are classified according to systems relating to abnormal locomotion, including hemiplegic gait, diplegic gait, neuropathic gait, myopathic gait, parkinsonian gait, choreiform gait, ataxic gait, and sensory gait.

[0286] Anesthesia / Sedation Anesthesia is a pharmacologically induced, reversible state of amnesia, analgesia, loss of responsiveness, loss of skeletal muscle reflexes, decreased stress response, or all of these simultaneously. These effects can be obtained from a single drug that provides the correct combination of effects alone, or sometimes using a combination of drugs (e.g., hypnotics, sedatives, paralytics, analgesics) to achieve a very specific combination of results. Anesthesia allows patients to undergo surgery and other procedures without the difficulty and pain they would otherwise experience.

[0287] Sedation is the reduction of irritability or agitation, typically through the administration of a pharmacological agent, to facilitate a medical or diagnostic procedure.

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

[0289] Minimal sedation is also known as anxiolysis. 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 responds purposefully to verbal commands, either alone or with light tactile stimulation. Interventions to maintain the patient's airway are usually not required. Spontaneous ventilation is typically adequate. Cardiovascular function is usually preserved.

[0291] Deep sedation / analgesia is a drug-induced decrease in consciousness from which the patient cannot be easily awakened but responds purposefully (rather than with a reflex withdrawal from painful stimuli) after repeated or painful stimulation. Independent ventilatory function may be impaired, so the patient may require assistance to maintain the patient's airway. Spontaneous ventilation may be inadequate. Cardiovascular function is usually preserved.

[0292] General anesthesia is a drug-induced loss of consciousness from which the patient cannot be aroused, even to painful stimuli. Assistance to maintain the patient's airway is often required because the ability to maintain independent ventilatory function is often impaired. Positive pressure ventilation may be required due to depressed spontaneous ventilation or drug-induced neuromuscular depression. Cardiovascular function may be impaired.

[0293] Sedation in the intensive care unit (ICU) allows patients to become less aware of their environment and less responsive to external stimuli. This can play a role in the treatment of critically ill patients and encompasses a wide range of symptom control that varies from patient to patient and individual to individual throughout the course of their illness. Heavy sedation in intensive care is used to facilitate endotracheal tube tolerance and ventilator synchronization (often with neuromuscular blockers).

[0294] In some embodiments, sedation (e.g., long-term sedation, continuous sedation) is induced in an ICU and maintained for an extended period of time (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months). Long-term sedatives may have a long duration of action. Sedatives in the ICU may have a short elimination half-life.

[0295] Procedural sedation and analgesia (also called conscious sedation) is the technique of administering sedatives or analgesics, with or without analgesics, to enable a subject to tolerate an uncomfortable procedure while maintaining cardiopulmonary function. [Example]

[0296] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic examples described herein are provided to illustrate the invention provided herein and should not be construed in any way 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 can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization.

[0298] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The selection of a suitable protecting group for a particular functional group and suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups and their introduction and removal are described in T.W. Greene and P.G.M. Buts, Protecting Groups in Organic Synthesis, 2nd Edition, Wiley, New York, 1991, and the references cited therein.

[0299] The compounds provided herein can be isolated and purified by known standard procedures. Such procedures include, but are not limited to, recrystallization, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following schemes are presented in detail for the preparation of representative oxysterols listed herein. The compounds provided herein can be prepared from known or commercially available starting materials and reagents by those skilled in the art of organic synthesis. Exemplary chiral columns available for use in the separation / purification of enantiomers / diastereomers provided herein include, but are not limited to, CHIRALPAK® AD-10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ, and CHIRALCEL® OK.

[0300] Exemplary general method for preparative HPLC: Column: Durashell. Mobile phase: A: water, B: acetonitrile. %B after 0 min: 41%, %B after 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% B in 1.6 or 2 min; Flow rate: 1.8 or 2 mL / min; Column: XBridge C18, 4.6 x 50 mm, 3.5 m, 45 °C

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

[0303] Exemplary LCMS conditions include: [Table A] [Table B] [Table C]

[0304] Steroid inhibition of TBPS binding Using rat brain cortical membranes in the presence of 5 mM GABA 35 S]-t-butylbicyclophosphorothionate (TBPS) binding assays have 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] Briefly, Sprague-Dawley rats (200-250 g) anesthetized with carbon dioxide were decapitated and the cortices were rapidly removed. The cortices were homogenized in 10 volumes of ice-cold 0.32 M sucrose using a glass / Teflon homogenizer and centrifuged at 1500 x g for 10 minutes at 4°C. The resulting supernatant was centrifuged at 10,000 x g for 20 minutes at 4°C to obtain a P2 pellet. The P2 pellet was resuspended in 200 mM NaCl / 50 mM Na-K phosphate pH 7.4 buffer and centrifuged at 10,000 x g for 10 minutes at 4°C. This washing procedure was repeated twice, and the pellet was resuspended in 10 volumes of buffer. Aliquots (100 mL) of the membrane suspension were diluted with 3 nM [ 35The cells were incubated with a 5 mL aliquot of test drug (0.5% final) dissolved in dimethyl sulfoxide (DMSO) in the presence of [S]-TBPS and 5 mM GABA. This incubation resulted in a final volume of 1.0 mL containing buffer. Nonspecific binding was measured in the presence of 2 mM unlabeled TBPS and ranged from 15 to 25%. After a 90-minute incubation at room temperature, the assay was terminated by filtration onto glass fiber filters (Schleicher and Schuell No. 32) using a cell harvester (Brandel) and rinsed three times with ice-cold buffer. Filter-bound radioactivity was measured by liquid scintillation spectrometry. Nonlinear curve fitting of the entire data set for each drug averaged over each concentration was performed using Prism (GraphPad). If the sum of squares was significantly low by F-test, the data were fitted to a partial inhibition model instead of a complete inhibition model. Similarly, if the sum of squares was significantly low by F-test, a two-component inhibition model was used instead of a one-component inhibition model. The concentration of test compound that results in 50% inhibition of specific binding (IC 50 ) and the maximum degree of inhibition (I max ) is determined for each individual experiment using the same model used for the entire data set, and the mean ± SEM for that individual experiment is then calculated. Picrotoxin serves as a positive control for these studies because it has been demonstrated to strongly inhibit TBPS binding.

[0306] Various compounds were tested in vitro 35 S]-TBPS binding. These assays are or can 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: Isopropylmagnesium 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: Dess-Martin periodinane; EtMgBr: ethyl magnesium bromide; EtOAc: 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: acetonitrile tolyl; 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: Isopropylmagnesium chloride; TBSCl: tert-butyl(chloro)dimethylsilane; (i-PrO)4Ti: Titanium tetraisopropoxide; BHT: 2,6-di-t-butyl-4-methylphenoxide; Me: Methyl; i-Pr: Iso- Propyl; t-Bu: tert-butyl; Ph: phenyl; Et: ethyl; Bz: benzoyl; BzCl: benzoyl chloride; CsF: cesium fluoride; DCC: dicyclohexylcarbodiimide; DCM: dichloromethane; DMAP: 4-dimethylaminopyridine; DMP: Dess-Martin periodinane; EtMgBr: ethyl magnesium bromide; EtOAc: ethyl acetate; TEA: triethylamine; AlaOH: alanine; Boc: t-butoxycarbonyl; Py: pyridine; TBAF: tetra-n-butylammonium fluoride THF: tetrahydrofuran; TBS: t-butyldimethylsilyl; TMS: trimethylsilyl; TMSCF3: (trifluoromethyl)trimethylsilane; Ts: p-toluenesulfonyl; Bu: butyl; Ti(OiPr)4: tetraisopropoxytitanium; LAH: lithium aluminum hydride; LDA: lithium diisopropylamide; LiOH.H2O: lithium hydroxide hydrate; MAD: methylaluminum bis(2,6-di-t-butyl-4-methylphenoxide); MeCN: acetonitrile; NBS: N-bromosuccinimide; Na2SO4: sodium sulfate; Na2S2O3: sodium thiosulfate; PE: petroleum ether; MeCN: acetonitrile; MeOH: methanol; Boc: t-butoxycarbonyl; MTBE: methyl tert-butyl ether; 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 (100 g, 290 mmol) in THF (500 mL) was added Pd-C (wet, 10%, 10 g) under N. The suspension was degassed under vacuum and purged with H three times. The mixture was then heated under H (15 psi) for 30 minutes. After stirring at 25° C. for 48 h, a black suspension was obtained. The reaction mixture was filtered through a pad of Celite and washed with THF (500 mL). The filtrate was concentrated to give 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 MePPhBr (20.6 g, 57.7 mmol, 1.0 equiv.) in THF (200 mL) was added t-BuOK (6.47 g, 57.7 mmol, 1.0 equiv.) at 0 °C. After the addition, the reaction mixture was heated to 20 °C and stirred for 1 h. Then, the mixture was added to a solution of A2 (20 g, 57.7 mmol, 1.0 equiv.) in THF (200 mL), and the reaction mixture was stirred at 20 °C for 2 h. The mixture was treated with NHCl (100 mL, 10%) and extracted with EtOAc (2 × 100 mL). The organic phase was separated and concentrated in vacuo to give the product as a crude residue. The residue was diluted with MeOH / H2O ( Trituration with 400 ml (1 / 1) at 20° C. gave a crude residue which was dissolved in DCM (200 mL), washed with saturated brine (2×50 mL), dried over anhydrous NaSO, filtered and concentrated to give 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) was added Pd—C (dry, 10%, 2 g) under N. The suspension was degassed under reduced pressure and purged with H three times. The mixture was stirred under H at 15 °C for 20 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give 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) was added K2CO3 (28.6 g, 207 mmol) in one portion at 15 °C under N2. The mixture was stirred at 15 °C for 2 h and quenched with water (100 mL). The aqueous phase was extracted with DCM (3 × 100 mL). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give 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) was added silica gel (11.2 g) and PCC (11.2 g, 52.6 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 1 h. The resulting mixture was filtered, and the filtrate was concentrated in vacuo. To a solution of this crude product in DCM (20 mL) was added silica gel (20 g) and PE (100 mL). After stirring at 25° C. for 30 min, the mixture was filtered, and the filtrate was concentrated in vacuo to give 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. A suspension of LiCl (2.05 g, 48.5 mmol, anhydrous) in THF (200 mL, anhydrous) was stirred at 10 °C under N for 30 min. FeCl (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 min, A6 (7 g, 23.1 mmol) was added at -30 °C. The mixture was stirred at -15 °C for 2 h and quenched with citric acid (200 mL, 10% aqueous solution). The mixture was extracted with EtOAc (2 × 100 mL). The combined organic phase was washed with saturated brine (300 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel column (PE / EtOAc = 0-10 / 1) to give A7 (1 g, 14%, Rf = 0.45 in PE / EtOAc) and A8 (0.8 g, 11%, Rf=0.40 (in PE / EtOAc) as well as the mixture (4 g) as a solid. 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 at C7 of A7 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 at C7 of A8 was confirmed by NOE.

[0325] Step 7a (Compound 1). To the over-dried bottom, t-BuOH (2 mL) and t-BuOK (703 mg, 6.27 mmol) were added. After evaporating and filling with N, a solution of A7 (200 mg, 0.627 mmol) in DME (1 mL) was added. After 30 min, 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 h and quenched with water. 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 NaSO and concentrated. The residue was purified by flash chromatography eluting with (petroleum ether / ethyl acetate = 10 / 1) to give 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), 10-80AB_3MIN_E.M, purity 100%, C 22 H 34 N[M+H-HO] + MS ESI calculated value 312, observed value 312.

[0328] Step 7b (Compound 2). In an oven-dried round-bottom flask, t-BuOH (2 mL) and t-BuOK (703 mg, 6.27 mmol) were added. The reaction vessel was evaporated and filled with N. 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. It 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 NaSO and concentrated. The residue was purified by flash chromatography eluting with (petroleum ether:ethyl acetate = 4:1) to give 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), 10-80AB_3MIN_E.M, purity 100%, C 22 H 34 NO[M+H-HO] + MS ESI calculated value 312, observed value 312.

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

[0332] Step 1a (B1). To a solution of A7 (200 mg, 0.627 mmol) in MeOH (5 mL) was added NaBH (47.2 mg, 1.25 mmol) at 25 °C. After stirring at 25 °C for 30 min, the reaction was quenched by the addition of water (10 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo to give 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) was added KOH (94.2 mg, 1.68 mmol) and MeSO (0.282 mg, 0.211 mL, 2.24 mmol) at 0 °C. The mixture was then warmed to 25 °C and stirred at the same temperature for 16 h. The mixture was quenched with 50 mL of water and extracted with EtOAc (2 × 30 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column (PE / EtOAc = 0 to 10 / 1) to give 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), 10-80AB_3MIN_E.M, purity 100%, C 22 H 37 O[M+H-HO] + MS ESI calculated value 317, observed value 317.

[0337] Step 1b (B2). To a solution of A8 (200 mg, 0.627 mmol) in MeOH (5 mL) was added NaBH (47.2 mg, 1.25 mmol) at 25 °C. After stirring at 25 °C for 30 min, the reaction was quenched by the addition of water (10 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo to give 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) was added KOH (88.6 mg, 1.58 mmol) and MeSO (0.266 mg, 0.2 mL, 2.11 mmol) at 0 °C. The mixture was then warmed to 25 °C and stirred at the same temperature for 16 h. The mixture was quenched by the addition of 50 mL of water and extracted with EtOAc (2 × 30 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column (PE / EtOAc = 0 to 10 / 1) to give 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), 10-80AB_3MIN_E.M, purity 100%, C 22 H 37 O[M+H-HO] + MS ESI calculated value 317, observed value 317.

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

[0342] Step 1. To a suspension of PPhEtBr (1.91 g, 5.15 mmol) in THF (10 mL) was added t-BuOK (0.577 g, 5.15 mmol) at 10 °C. The suspension turned dark red. After stirring at 40 °C for 30 min, 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 h, the reaction mixture was poured onto 20 g of crushed ice and stirred for 15 min. The organic layer was separated, and the aqueous phase was extracted with EtOAc (2 × 20 mL). The combined organic phases were washed with saturated brine (2 × 20 mL), dried over anhydrous NaSO, filtered, concentrated, and purified by flash column chromatography (0–10% EtOAc in PE) to give 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) was added dropwise a solution of BH3-Me2S (0.605 mL, 6.05 mmol) at 0 °C. The solution was stirred at 15 °C for 3 h. After cooling to 0 °C, NaOH solution (3.62 mL, 2 M) was added very slowly. After the addition, H2O2 (683 mg, 6.05 mmol) was added. C. The resulting mixture was extracted with EtOAc (3.times.50 mL). The combined organic solution was washed with saturated aqueous Na.sub.2S.sub.2O.sub.3 (2.times.20 mL), brine (20 mL), dried over Na.sub.2SO.sub.4, and concentrated in vacuo to give the 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) was added silica gel (222 mg) and PCC (222 mg, 1.03 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 1 h. The resulting mixture was filtered, and the filtrate was concentrated in vacuo. To a solution of the crude product in DCM (20 mL), silica gel (20 g) and PE (100 mL) were added. The mixture was stirred at 25 °C for 30 min, filtered, and the filtrate was concentrated in vacuo to give the crude product, which was purified by flash column (0-10% EtOAc in PE) to give 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), 10-80AB_3MIN_E.M, purity 100%, C 23 H 37 O[M+H-HO] + MS ESI calculated value 329, found value 329.

[0349] Step 4. To a suspension of PPhEtBr (1.21 g, 3.27 mmol) in THF (10 mL) was added t-BuOK (0.366 g, 3.27 mmol) at 10 °C. The suspension turned dark red. After stirring at 40 °C for 30 min, 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 h. The reaction mixture was poured onto 20 g of crushed ice and stirred for 15 min. The organic layer was separated, and the aqueous phase was extracted with EtOAc (2 × 20 mL). The combined organic phases were washed with saturated brine (2 × 20 mL), dried over anhydrous NaSO, filtered, concentrated, and purified by flash column (0–10% EtOAc in PE) to give 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) was added dropwise a solution of BH3-Me2S (0.363 mL, 3.63 mmol) at 0 °C. The solution was stirred at 15 °C for 3 h. After cooling to 0 °C, NaOH solution (2.17 mL, 2 M) was added very slowly. After the addition, H2O2 (410 mg, 3.63 mmol, 30% in water) was added slowly, maintaining the internal temperature below 10 °C. The resulting solution was stirred at 15 °C for 2 h. Then, saturated aqueous Na2S2O3 solution (50 mL) was added until the reaction solution became clear. The mixture was extracted with EtOAc (3 × 50 mL). The combined organic solution was washed with saturated aqueous Na2S2O3 (2 x 20 mL), brine (20 mL), dried over Na2SO4 and concentrated in vacuo to give the 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) was added silica gel (123 mg) and PCC (123 mg, 0.572 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 1 h. 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. The mixture was stirred at 25 °C for 30 min, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by flash column (0-10% EtOAc in PE) to give 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), 10-80AB_3MIN_E.M, purity 100%, C 23 H 37 O[M+H-HO] + MS ESI calculated value 329, found value 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 PPhEtBr (72.7 g, 196 mmol) in THF (200 mL) was added t-BuOK (21.9 g, 196 mmol) at 10 °C. The suspension turned dark red. After stirring at 40 °C for 30 min, a solution of A5 (20 g, 65.6 mmol) in THF (20 mL) was added at 40 °C, and the reaction mixture was stirred at 40 °C for 1 h. The reaction mixture was poured onto 200 g of crushed ice and stirred for 15 min. The organic layer was separated, and the aqueous phase was extracted with EtOAc (2 × 200 mL). The combined organic phases were washed with saturated brine (2 × 200 mL), dried over anhydrous NaSO, filtered, concentrated, and purified by flash column (0–30% EtOAc in PE) to give D1 (19.5 g, 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) was added silica gel (10 g) and PCC (13.5 g, 63.0 mmol). The mixture was stirred at 15 °C for 2 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by flash column (0-30% EtOAc in PE) to give 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 in one portion. The mixture was stirred for 30 minutes to obtain a clear solution. To this solution, anhydrous FeCl3 (7.44 g, 45.9 mmol) was added in one portion. The resulting mixture was stirred for an additional 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 in one portion. The internal temperature was brought 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, 200 mL) and extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with water (200 mL), aqueous NaOH (10%, 2 × 200 mL), and brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc = 20 / 1 to 20 / 1) to give 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. To a solution of D3 (6 g, 18.1 mmol) in THF (85 mL) was added 9-BBN dimer (13.2 g, 54.3 mmol). The mixture was stirred at 50 °C for 2 h. 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, HO (18.1 mL, 181 mmol, 30%) was added slowly to maintain the internal temperature below 15 °C. The resulting solution was stirred at 75 °C for 1 h. The mixture was cooled and added to water (100 mL). The aqueous phase was extracted with EtOAc (3 × 100 mL). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated to give D4 (5.9 g, crude) as a colorless oil, which was used directly for the next step without purification.

[0364] Step 5. To a suspension of D4 (5.9 g, 16.9 mmol) in DCM (100 mL) was added silica gel (3 g) and PCC (5.45 g, 25.3 mmol) at 15° C. The mixture was stirred at 15° C. for 2 h. The mixture was filtered, and the filtered cake The cake) was washed with DCM (50 mL). The combined filtrate was concentrated in vacuo and purified by flash column (0-30% EtOAc in PE) to give 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) was added HBr (57.4 mg, 0.29 mmol, 40% in water) and Br2 (337 mg, 2.15 mmol) at 25° C. The mixture was stirred at 25° C. for 2 hours. The mixture was quenched with saturated aqueous NaHCO (10 mL), treated with water (20 mL), and extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to afford D6 (480 mg, crude) as a pale yellow oil, 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) was added NaH (89.5 g, 2.24 mmol, 60%) in portions at 25 °C. The mixture was stirred at 60 °C for 10 min. Then, D6 (480 mg, 1.12 mmol) in THF (10 mL) was added dropwise to the solution. The mixture was stirred at 60 °C for 1 h. The mixture was poured into water (50 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layer was washed with brine (50 mL), dried over NaSO, and concentrated to give the crude product. The residue was purified by silica gel chromatography (100–200 mesh silica gel, petroleum ether / ethyl acetate = 0 / 1) to give 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% NH / HO, B = EtOH), flow rate: 80 mL / min) to give 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 min chromatography), 30-90AB_2MIN_E, purity 100%, C 29 H 42 N3O2[M+H] + MS ESI calculated value 464, found value 464.

[0371] SFC Rt=1.785 min (3 min 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 min chromatography), 30-90AB_2MIN_E, purity 98%, C 29 H 42 N3O2[M+H] + MS ESI calculated value 464, found value 464.

[0374] SFC Rt=2.132 min (3 min 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) was added HBr (57.4 mg, 0.288 mmol, 40% in water) and Br2 (229 mg, 1.46 mmol) at 25 °C. The mixture was stirred at 25 °C for 16 h. The mixture was quenched with saturated aqueous NaHCO3 (10 mL), treated with water (20 mL), and extracted with EtOAc (2 × 20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give D6 (500 mg, crude) as a solid, which was used directly for the next step.

[0376] Step 2 (Compounds 7 and 8): To a mixture of D6 (500 mg, 1.17 mmol) and KCO (323 mg, 2.34 mmol) in acetone (3 mL) was added 1H-pyrazolo[3,4-c]pyridine (1.45 mg, 1.22 mmol) at 25° C. The mixture was stirred at 25° C. for 12 hours. The mixture was poured into water (50 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified by preparative HPLC separation (column: Phenomenex Synergi C18 150 x 30 mm x 4 um) with a gradient of 28-58% B (A = 0.1% HCl, B = ACN), flow rate: 30 mL / min, followed by SFC (column: OJ (250 mm x 30 mm, 10 um) with a gradient of 35-35% B (A = 0.1% NH3HO, B = ETOH), flow rate: 80 mL / min) to give compound 8 (15 mg, 75% yield) as a solid and compound 7 (5 mg, 25% yield) 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 min chromatography), 10-80AB.lcm, purity 99.7%, C 29 H 42 N3O2[M+H] + MS ESI calculated value 464, found value 464.

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

[0382] Step 1. To a solution of chloro(methoxymethyl)triphenylphosphorane (19.7 g, 57.7 mmol) in THF (200 mL) was added t-BuLi (44.3 mL, 57.7 mmol, 1.3 M in n-hexane) at -10 °C. After the addition, the reaction mixture was stirred for 1 h. Then, A2 (20 g, 57.7 mmol) in THF (200 mL) was added at 0 °C, and the reaction mixture was stirred at 15 °C for 2 h. The mixture was treated with NH4Cl (100 mL, 10%), and EtOAc (2 × 200 mL) was added. The organic phase was separated and concentrated in vacuo to give the crude product. The residue was purified by flash column (0 to 30% EtOAc in PE) to give 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) was added Pd—C (dry, 10%, 1 g) under N. The suspension was degassed under reduced pressure and purged with H three times. The mixture was stirred at 15 °C under H (15 psi) for 16 h to give a black suspension. The reaction mixture was filtered through a pad of Celite and washed with EtOH (3 × 20 mL). The filtrate was concentrated to give 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) was added K2CO3 (5.52 g, 40.0 mmol) in one portion at 15 °C under N2. The mixture was stirred at 15 °C for 2 h. 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 Drying over SO4, filtration and concentration gave E3 (3 g, 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 PPhEtBr (11.5 g, 31.2 mmol) in THF (50 mL) was added t-BuOK (3.5 g, 31.2 mmol) at 10 °C. The suspension turned dark red. After stirring at 40 °C for 1 h, 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 h. Saturated NHCl solution (20 mL) was added to the mixture, which was then extracted with EtOAc (2 × 20 mL). The organic layer was separated, and the aqueous phase was extracted with EtOAc (2 × 10 mL). The combined organic phases were washed with saturated brine (2 × 20 mL), dried over anhydrous NaSO, filtered, concentrated, and purified by flash column chromatography (0–30% EtOAc in PE) to give 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 at C7 of E4 was confirmed by NOE.

[0391] Step 5. To a suspension of E4 (1.5 g, 4.32 mmol) in DCM (30 mL) was added silica gel (2 g) and PCC (1.86 g, 8.64 mmol) at 15 °C. The mixture was stirred at 15 °C for 2 h. The mixture was filtered, and the filter cake was washed with DCM (2 × 20 mL). The combined filtrate was concentrated in vacuo and purified by flash column (0 to 30% EtOAc in PE) to give 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 in one portion. The mixture was stirred for 30 minutes to obtain a clear solution. To this solution, anhydrous FeCl3 (1.24 g, 7.65 mmol) was added in one portion. The resulting mixture was stirred for an additional 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 in one portion. The internal temperature was brought 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 EtOAc (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 by column chromatography on silica gel (PE / EtOAc = 20 / 1 to 5 / 1) to give 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) was added dropwise a solution of BH3-Me2S (2.77 mL, 27.7 mmol, 10 M in THF) at 0 °C. The solution was stirred at 15 °C for 3 h. After cooling to 0 °C, NaOH solution (16.6 mL, 2 M) was added very slowly. After the addition, H2O2 (2.76 mL, 27.7 mmol, 30% in water) was added slowly to maintain the internal temperature below 10 °C. The resulting solution was stirred at 15 °C for 2 h. Then, saturated aqueous Na2S2O3 solution (20 mL) was added until the reaction solution became clear. The mixture was extracted with EtOAc (3 × 20 mL). The combined organic solution was washed with saturated aqueous NaS0 (2 x 10 mL), brine (20 mL), dried over NaSO and concentrated in vacuo to give E7 (0.9 g, crude) as a solid, which was used in the next step without further purification.

[0396] Step 8. To a suspension of E7 (0.9 g, 1.37 mmol) in DCM (20 mL) was added silica gel (1 g) and PCC (1.02 g, 4.74 mmol) at 15 °C. The mixture was stirred at 15 °C for 2 h. The mixture was filtered, and the filter cake was washed with DCM (2 × 20 mL). The combined filtrate was concentrated in vacuo, purified by flash column (0-20% EtOAc in PE), and recrystallized from DCM / n-hexane (2 mL / 20 mL) at 15 °C to give 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 min chromatography), 30-90AB_2MIN_E, purity 87%, C 24 H 39 O2 [M+H-H2O] + MS ESI calculated value 359, found value 359.

[0399] HPLC Rt=4.54 min (8 min 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 PPhEtBr (26.5 g, 71.6 mmol) in THF (100 mL) was added t-BuOK (8.03 g, 71.6 mmol) at 10 °C. The suspension turned dark red. After stirring at 40 °C for 1 h, 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 h. To the mixture was added saturated NHCl solution (20 mL) and EtOAc (2 × 30 mL). The organic layer was separated, and the aqueous phase was extracted with EtOAc (2 × 30 mL). The combined organic phases were washed with saturated brine (2 × 20 mL), dried over anhydrous NaSO, filtered, concentrated, and purified by flash column (0–20% EtOAc in PE) to give 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 at C7 of F1 was confirmed by NOE.

[0404] Step 2. To a solution of F1 (2 g, 5.77 mmol) in DCM (50 mL) was added DMP (4.87 g, 11.5 mmol). The reaction was then stirred at 15 °C for 30 min. Saturated aqueous NaHCO (50 mL), saturated aqueous NaSO (50 mL) were added to the reaction mixture, and it was extracted with DCM (2 × 50 mL). The combined organic layers were washed with saturated aqueous NaHCO (2 × 20 mL) and brine (20 mL), dried over NaSO, filtered, and concentrated in vacuo to give 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 in one portion. The 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 resulting mixture was stirred for an additional 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 above 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 in one portion. The internal temperature was brought 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 EtOAc (2 x 20 mL). The combined organic layers were washed with water (20 mL), aqueous NaOH (10%, 2 x 20 mL), and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column (0-30% EtOAc in PE) to give F3 (1.6 g, 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) was added dropwise a solution of BH3-Me2S (4.43 mL, 44.3 mmol, 10 M in THF) at 0 °C. The solution was stirred at 15 °C for 3 h. After cooling to 0 °C, NaOH solution (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 added slowly to maintain the internal temperature below 10 °C. The resulting solution was stirred at 15 °C for 2 h. Then, saturated aqueous Na2S2O3 solution (20 mL) was added until the reaction solution became clear. The mixture was extracted with EtOAc (3 × 20 mL). The combined organic solution was washed with saturated aqueous Na2S2O3 (2 x 10 mL), brine (20 mL), dried over Na2SO4 and concentrated in vacuo to give F4 (1.66 g, crude) as a solid, which was used in the next step without further purification.

[0409] Step 4. To a solution of F4 (1.66 g, 4.4 mmol) in DCM (50 mL) was added DMP (3.73 g, 8.80 mmol) at 15 °C. The reaction was stirred at 15 °C for 10 min. Saturated aqueous NaHCO (50 mL), saturated aqueous NaSO (50 mL) were added to the reaction mixture, and it was extracted with DCM (2 × 20 mL). The combined organic layer was washed with saturated aqueous NaHCO (3 × 20 mL) and brine (20 mL), dried over NaSO, filtered, concentrated in vacuo, and purified by silica gel chromatography (PE / EtOAc = 15 / 1 to 10 / 1) to give 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 give 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 min chromatography), 30-90AB_2MIN_E, purity 100%, C 24 H 39 O2 [M+H-H2O] + MS ESI calculated value 359, found value 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 Br (131 mg, 0.835 mmol) were added at 25 °C. The mixture was stirred at 25 °C for 16 hours and quenched by the addition of saturated aqueous NaHCO (10 mL) and water (20 mL). The mixture was extracted with EtOAc (2 × 20 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 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) was added 1H-pyrazole-4-carbonitrile (18.2 mg, 0.196 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h and treated with HO (50 mL). The mixture was extracted with EtOAc (3 × 50 mL). The combined organic solution was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified twice by flash column (0 to 30% EtOAc in PE) to give 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 min chromatography), 30- 90AB_2MIN_E.M.lcm, 100% purity, C 28 H 42 N3O3[M+H] + MS ESI calculated value 468, found value 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 Br (304 mg, 1.94 mmol) were added at 25 °C. After stirring at 25 °C for 16 h, the mixture was quenched with saturated aqueous NaHCO (10 mL) and water (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 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) was added 1H-pyrazole-4-carbonitrile (24.3 mg, 0.262 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h, treated with HO (50 mL), and extracted with EtOAc (3 × 50 mL). The combined organic solution was washed with brine (20 mL), dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified by flash column (0-30% EtOAc in PE) to give 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=2.901 min (in) (4.0 min 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) was added 5-methoxy-2H-benzo[d][1,2,3]triazole (98.1 mg, 0.658 mmol) followed by K2CO3 (121 mg, 0.878 mmol) at 25 °C. The resulting reaction mixture was stirred at 25 °C for 16 h, treated with water (20 mL), and extracted with EtOAc (3 × 20 mL). The combined organic solution was washed with brine (20 mL), dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified by flash column (0–30% EtOAc in PE) to give impure compound 15 (50 mg). The impure compound 15 was purified by preparative HPLC (column: YMC-Actus Triart C18 150 × 30 mm × 5 μm), gradient: 65–95% B (A = water (0.05% HCl)-ACN, B = ACN), flow rate: 25 mL / min) to give compound 15 (18 mg, 8%) as a solid; a mixture of compound 16 and compound 17 (100 mg, crude) was obtained. The mixture of compound 16 and compound 17 (100 mg, crude) was purified by SFC (column: OJ (250 mm × 30 mm, 5 μm)), gradient: 40–40% B (A = 0.1% NH3HO, B = ETOH), flow rate: 60 mL / min) to give compound 16 (33 mg, 14%) as a solid, and compound 17 (16 mg, 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), 10-80AB.lcm, purity 100%, C 31 H 46 N3O4[M+H] + MS ESI calculated value 524, observed value 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) was added 5-methoxy-2H-benzo[d][1,2,3]triazole (98.1 mg, 0.658 mmol) followed by K2CO3 (121 mg, 0.878 mmol) at 25 °C. The resulting reaction mixture was stirred at 25 °C for 16 h, treated with water (20 mL), and extracted with EtOAc (3 × 20 mL). The combined organic solution was washed with brine (20 mL), dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified by flash column chromatography (0–30% EtOAc in PE) to give compound 18 (10 mg, 4%) as a solid and a mixture of compound 19 and compound 20 (100 mg, crude). The mixture of compound 19 and compound 20 was purified by SFC separation (column: OD (250 mm × 30 mm, 5 um)), gradient: 40-40% B (A = 0.1% NH3HO, B = ETOH), flow rate: 50 mL / min) to give 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), 10-80AB.lcm, 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] + MS ESI calculated value 524, observed value 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) was added K2CO3 (26.1 g, 0.658 mmol) at 25 °C. After stirring at 25 °C for 10 h, the mixture was poured into water (50 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to give the crude product, which 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 give 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% EtOAc in PE) to give 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, 1H), 0.73 (s, 6H).

[0443] LCMS Rt=1.771 min (3.0 min chromatography), 10-80AB, 100% purity, C 30 H 44 N3O3[M+H] + MS ESI calculated value 494, found value 494.

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

[0445] To a mixture of H1 (150 mg, 0.329 mmol) and K2CO3 (90.9 mg, 0.658 mmol) in acetone (3 mL) was added 1H-pyrazolo[3,4-c]pyridine (41 mg, 0.345 mmol) at 25 °C. After stirring at 25 °C for 12 h, the mixture was poured into water (50 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to give the crude product, which 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 give 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% NH3HO, B = EtOH), flow rate: 80 mL / min) to give 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] + MS ESI calculated value 494, found value 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] + MS ESI calculated value 494, found value 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) was added K-selectride (57.7 mL, 57.7 mmol, 1 M in THF) dropwise at −70° C. The reaction mixture was stirred at −70° C. for 2 h. The mixture was quenched with saturated NH4Cl (20 mL) at −20° C. and extracted with EtOAc (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% EtOAc in PE) to give 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) was added TBSOTf (11.8 mL, 51.6 mmol) and 2,6-dimethylpyridine (7.37 g, 68.8 mmol) in one portion at 15 °C. The mixture was refluxed at 15 °C for 7 h. Saturated NH4Cl (50 mL) was then added to the reaction mixture. The aqueous phase was extracted with DCM (3 × 50 mL). The combined organic phase was washed with brine (2 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue, which was purified by flash column (0–5% EtOAc in PE) to give I2 (8.35 g, crude) as an oil, which 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 of I2, t-BuOK (11.4 g, 102 mmol) was added at 10 °C. The suspension turned dark red. After stirring at 40 °C for 1 h, 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 h. To the mixture, saturated NH4Cl solution (20 mL) and EtOAc (60 mL) were added. The organic layer was separated, and the aqueous phase was extracted with EtOAc (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% EtOAc in PE) to give 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) was added DMP (23.4 g, 55.4 mmol), followed by HO (2.48 mg, 0.138 mmol). The reaction mixture was stirred at 15 °C for 30 min. Saturated aqueous NaHCO (50 mL), saturated aqueous NaSO (50 mL) were added to the reaction mixture, and it was extracted with DCM (2 × 50 mL). The combined organic layers were washed with saturated aqueous NaHCO (2 × 20 mL) and brine (20 mL), dried over NaSO, filtered, concentrated in vacuo, and purified by flash column (0-10% EtOAc in PE) to give 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 in one portion. The mixture was stirred for 30 minutes to obtain a clear solution. To this solution, anhydrous FeCl3 (4.94 g, 30.5 mmol) was added in one portion. The resulting mixture was stirred for an additional 30 minutes. The reaction mixture was cooled to -35°C, and methylmagnesium bromide (3 M in diethyl ether, 37.0 mL, 111 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. I4 (6 g, 13.9 mmol) in THF (20 mL) was added in one portion. The internal temperature was brought to 15°C, and the reaction mixture was stirred for 2 hours. The reaction mixture was poured into ice-cold aqueous HCl (1 M, 20 mL) and extracted with EtOAc (2 x 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 by flash column (0-5% EtOAc in PE) to give 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) was added BH3.Me2S (7.83 mL, 10 M, 78.3 mmol) dropwise at 0 °C. The resulting solution was stirred at 15 °C for 3 h. After cooling to 0 °C, aqueous NaOH (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 added slowly to maintain the internal temperature below 10 °C. The resulting solution was stirred at 15 °C for 1 h. Then, saturated aqueous Na2S2O3 (20 mL) was added until the reaction solution became clear. The mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with saturated aqueous Na2S2O3 (2 x 10 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to give 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) was added DMP (6.19 g, 14.6 mmol) followed by HO (2.62 mg, 0.146 mmol). The reaction mixture was stirred at 15 °C for 30 min. Saturated aqueous NaHCO (50 mL) and saturated aqueous NaSO (10 mL) were added to the reaction mixture. The mixture was extracted with DCM (2 × 20 mL). The combined organic layers were washed with saturated NaHCO (2 × 20 mL) and brine (20 mL), dried over NaSO, filtered, concentrated in vacuo, and purified by flash column (0-10% EtOAc in PE) to give 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 CHOH (50 mL) was added concentrated HCl (0.966 mL, 12 M) at 15 °C under N. The mixture was stirred at 15 °C for 16 h. Saturated NaHCO (5 mL) was added to the mixture and stirred for 20 min. The aqueous phase was extracted with EtOAc (3 × 50 mL). The combined organic phase was washed with brine (2 × 50 mL), dried over anhydrous NaSO, filtered, and concentrated to give a solid, which was purified by flash column (0 to 70% EtOAc in PE) to give compound 25 (1.20 g, impure) as a solid. Impure compound 25 (600 mg, impure) was triturated with hexane (30 mL) at 68 °C to give 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, observed 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) was added HBr (57.2 mg, 0.284 mmol, 40% in water) and Br (230 mg, 1.75 mmol) at 15 °C. After stirring at 15 °C for 4 h, the mixture was quenched with NaHCO (10 mL), treated with water (20 mL), and extracted with EtOAc (3 × 20 mL). The combined organic phase was washed with brine (40 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give 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. The mixture was stirred at 25 °C for 16 hours. The mixture was concentrated to give a pale yellow solid. The solid was purified by preparative HPLC (column: YMC-Actus Triart C18 100 × 30 mm × 5 μm; conditions: water (0.05% HCl)-ACN; gradient 53% to 83% B; gradient time (min): 9.5) to give 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 min chromatography), 5-95AB, 100% purity, C 26 H 34 NO[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) was added J1 (300 mg, 0.701 mmol) at 15 °C under N2. The mixture was stirred at 15 °C for 16 h. The mixture was filtered and concentrated to give a solid, which was purified by preparative HPLC (Xtimate C18 150 × 25 mm × 5 μm column; conditions: water (0.05% HCl)-ACN; gradient 16% to 41% B; gradient time (min): 9.5) to give compound 27 (8.00 mg, 2%) and compound 28 (6.00 mg, 2%) as solids.

[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 min chromatography), 5-95AB, 100% purity, C 28 H 40 N3O3[M+H] + MS ESI calculated value 466, found value 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 min chromatography), 5-95AB, 100% purity, C 28 H 40 N3O3[M+H] + MS ESI calculated value 466, found value 466.

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

[0477] Step 1. To a solution of A3 (82 g, 269 mmol) in DCM (500 mL) was added imidazole (27.4 g, 403 mmol) and TBSCl (60.7 g, 403 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 5 h. The reaction mixture was concentrated under reduced pressure. The residue was triturated with MeOH (500 mL) to give 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) was added L-selectride (65.6 mL, 1 M in THF, 65.6 mmol) at −70° C. under N2. The reaction mixture was stirred at −70° C. for 5 h. The reaction mixture was quenched with water (50 mL). The mixture was extracted with EtOAc (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 / EtOAc = 30 / 1 to 3 / 1) to give 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 EtPPhBr (39.3 g, 106 mmol) in THF (100 mL) was added t-BuOK (11.8 g, 106 mmol) at 25 °C under N2. The reaction mixture was stirred at 25 °C for 0.5 h. K2 (15 g, 35.6 mmol) was added to the reaction mixture under N2. The reaction mixture was stirred at 50 °C for 5 h. The reaction mixture was quenched with water (50 mL). The mixture was extracted with EtOAc (3 × 150 mL). The combined organic phases were washed with brine (2 × 50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EtOAc = 30 / 1 to 10 / 1) to give K3 (5.5 g, 36%) and K 3 (6 g, 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 (5 g, 11.5 mmol) in THF (50 mL) was added NaH (2.28 g, 60%, 57.4 mmol) at 0 °C. The reaction mixture was stirred at 0 °C under N for 0.5 h. MeI (44 g, 309 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was stirred at 40 °C for 20 h. The reaction mixture was quenched with ice-water (30 mL) and stirred for 20 min. The aqueous phase was extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with brine (2 × 50 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography (PE / EtOAc = 50 / 1 to 10 / 1) to give 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) was added TBAF (12 mL, 1 M in THF, 12.0 mmol) at 25 °C, and the reaction mixture was stirred at 40 °C for 15 h. The reaction mixture was quenched with water (20 mL), and the aqueous phase was extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with brine (2 × 30 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was triturated from water (40 mL) at 80 °C to give 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) was added silica gel (4 g) and PCC (1.68 g, 7.8 mmol) at 25 °C. The mixture was stirred at 25 °C for 3 h. The mixture was filtered through a pad of silica gel, and the solid was washed with EtOAc / DCM (30 / 30 mL), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 10 / 1 to 1 / 1) to give 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 in one portion. The mixture was stirred for 30 minutes to give a clear solution. To this solution was added anhydrous FeCl3 (1.07 g, 6.64 mmol) in one portion. The resulting mixture was stirred for an additional 30 minutes. The 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) was added dropwise. (mmol) was added in one portion. The internal temperature was brought to -20 °C and maintained between -15 and -20 °C for 2 h. The reaction mixture was poured into ice-cold aqueous HCl (1 M, 50 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were 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 column chromatography on silica gel (PE / EtOAc = 20 / 1 to 2 / 1) to give 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) was added BH3.Me2S (2.3 mL, 10 M in THF, 23 mmol) slowly at 0 °C under N2. The reaction mixture was stirred at 25 °C for 12 h. After the mixture was cooled to 0 °C, NaOH solution (7.66 mL, 3 M in HO, 23.0 mmol) was added very slowly to the mixture. After the addition was complete, HO2 (2.6 g, 30%) was added slowly, maintaining the internal temperature below 10 °C. The mixture was stirred at 25 °C for 2 h. The resulting solution was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with aqueous Na2S2O3 (40 mL), brine (50 mL), and dried over Na2SO4. The mixture was filtered. The filtrate was concentrated in vacuo to give 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) was added silica gel (1.71 g) and PCC (0.765 g, 3.56 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 4 h. The solution was filtered and the filter cake was washed with EtOAc (10 mL). The solution was filtered and the filter cake was washed with EtOAc (30 mL). The solution was concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EtOAc = 50 / 1 to 1 / 1) to give 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 min chromatography), 30-90AB_ELSD, purity 97.6.0%, C 22 H 33 O[M-H2O-CH3OH] + MS ESI calculated value 313, observed value 313.

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

[0496] Step 1. To a solution of K1 (15 g, 35.8 mmol) in THF (100 mL) was added LiAlH(t-BuO) (27.2 g, 107 mmol) at −70° C., and the reaction mixture was stirred at −70° C. for 5 h. The reaction mixture was poured into ice water (50 mL) and stirred for 20 min. The organic layer was separated. The aqueous phase was extracted with EtOAc (2×50 mL). The combined organic phases were washed with saturated brine (2×30 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash column (0-10% EtOAc in PE) to give L1 (8 g, 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)triphenylphosphorane (28.2 g, 76.0 mmol) in THF (100 mL) was added t-BuOK (8.52 g, 76.0 mmol) at 25 °C. The mixture was heated to 60 °C and stirred for 1 h. A solution of L1 (8 g, 19.0 mmol) in THF (20 mL) was added. The mixture was stirred at 60 °C for 16 h. The mixture was treated with NH4Cl (50 mL, saturated aqueous solution). The organic layer was separated. The aqueous phase was extracted with EtOAc (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% EtOAc in PE) to give 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 (5 g, 11.5 mmol) in THF (50 mL) was added NaH (2.28 g, 57.4 mmol, 60% in mineral oil) in one portion at 0 °C under N2. After 30 min, MeI (16.1 g, 114 mmol) was added dropwise at 20 °C. The reaction mixture was stirred at 40 °C for 6 h. The mixture was quenched with saturated aqueous NH4Cl (20 mL, saturated aqueous solution) at 0 °C. The organic layer was separated. The aqueous phase was extracted with EtOAc (2 × 20 mL). The combined organic phases were washed with saturated brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give 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) was added TBAF (55.5 mL, 55.5 mmol, 1 M in THF). The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was poured into water (50 mL). The organic layer was separated. The aqueous phase was extracted with EtOAc (2 × 20 mL). The combined organic phases were washed with saturated brine (2 × 20 mL), dried over anhydrous NaSO, filtered, and concentrated to give 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) was added silica gel (3 g) and PCC (4.64 g, 21.6 mmol) at 20 °C. The mixture was stirred at 20 °C for 2 h. The mixture was filtered, and the filter cake was washed with DCM (2 × 10 mL). The combined filtrate was concentrated in vacuo to give L5 (3 g, crude) as a solid.

[0504] Step 6. Under N2, anhydrous THF (10 mL) was cooled to 15 °C and anhydrous LiCl (1.53 g, 36.2 mmol) was added in one portion. The mixture was stirred for 30 minutes to give a clear solution. To this solution was added anhydrous FeCl3 (3.22 g, 19.9 mmol) in one portion. The resulting mixture was stirred for an additional 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 in one portion. The internal temperature was brought 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 EtOAc (2 × 20 mL). The organic layer was separated. 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 by flash column (0–10% EtOAc in PE) to give 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. To a solution of L6 (2.8 g, 8.07 mmol) in THF (15 mL) was added dropwise a solution of BH3.Me2S (8.07 mL, 10 M, 80.7 mmol) at 0 °C. The solution was stirred at 15 °C for 3 h. 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 added slowly to maintain the internal temperature below 10 °C. The resulting solution was stirred at 15 °C for 2 h. Saturated aqueous Na2S2O3 solution (20 mL) was then added until the reaction solution became clear. The mixture was extracted with EtOAc (3 × 20 mL). The combined organic solution was washed with saturated aqueous Na2S2O3 solution (2 × 10 mL), brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give 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) was added PCC (3.65 g, 17.0 mmol) and silica gel (3 g) at 25 °C. The solution was stirred at 25 °C for 3 h. The reaction mixture was filtered, and the filter cake was washed with anhydrous DCM (2 × 20 mL). The combined filtrate was concentrated in vacuo. The residue was purified by flash column (0 to 20% EtOAc in PE) to give compound 30 (2 g, impure) as a solid. The residue, compound 30 (2 g, 5.51 mmol), was recrystallized from MeCN (20 mL) at 65 °C to give compound 30 (24 mg, 1%, pure) as a solid. The mother liquor was concentrated to give 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 R =0.905 min (2 min chromatography), 30-90AB_ELSD, purity 100.0%, C 22 H 33 O[M-H2O-CHO] + MS ESI calculated value 313, observed value 313.

[0510] Step 9. To a solution of compound 30 (200 mg, 551 μmol) in MeOH (10 mL) was added HBr (11.1 mg, 0.0551 mmol, 40% in water) and Br (105 mg, 0.661 mmol) at 25 °C. The mixture was stirred at 25 °C for 2 hours. The mixture was quenched with saturated aqueous NaHCO (10 mL) and treated with water (20 mL). The mixture was extracted with DCM (2 × 20 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give L8 (230 mg, crude) as a pale yellow oil, 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) was added K2CO3 (143 mg, 1.04 mmol) and 1H-pyrazole-4-carbonitrile (58.1 mg, 0.625 mmol) at 25 °C. The mixture was stirred at 25 °C for 16 h. The mixture was treated with water (20 mL). The mixture was extracted with DCM (2 × 10 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column (0-50% EtOAc in PE) to give 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 R =0.912 min (2 min chromatography), 30-90AB_ELSD, purity 100.0%, C 27 H 40 N3O3[M+H] + MS ESI calculated value 454, found value 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 Br (551 mg, 3.45 mmol) were added at 25 °C. The mixture was stirred at 25 °C for 3 hours. The mixture was quenched with saturated aqueous NaHCO (10 mL), treated with water (20 mL), and extracted with EtOAc (2 × 30 mL). The combined organic phases were washed with saturated NaSO (50 mL) and brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography eluting with (petroleum ether / ethyl acetate = 5 / 1) to give 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) was added K2CO3 (161 mg, 1.17 mmol) and 5-methyl-2H-tetrazole (59.2 mg, 0.705 mmol). The mixture was stirred at 25 °C for 16 hours. Water (10 mL) and ethyl acetate (20 mL) were added to the 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 in vacuo. The residue was purified by flash chromatography eluting with (petroleum ether / ethyl acetate = 2 / 1) to give 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] + MS ESI calculated value 429, found value 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] + MS ESI calculated value 429, found value 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) was added HBr (126 mg, 0.634 mmol, 40% in water) and Br (608 mg, 3.80 mmol) at 25 °C. The mixture was stirred at 25 °C for 1 h. The mixture was quenched with saturated NaHCO (20 mL) and treated with water (20 mL). The mixture was extracted with DCM (2 × 30 mL). The combined organic phase was washed with brine (2 × 20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give N (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. To a solution of N3 (350 mg, 0.822 mmol) in acetone (10 mL) To the resulting solution, 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 h. The reaction mixture was treated with water (20 mL). The mixture was extracted with CHCl2 (2 × 20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column (0 to 100% EtOAc in PE) to give 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 min chromatography), 30-90AB_ELSD, purity 100.0%, C 25 H 41 N4O2[M+H] + MS ESI calculated value 429, found value 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 min chromatography), 30-90AB_ELSD, purity 100.0%, C 25 H 39 NO[M+H-HO] + MS ESI calculated value 411, observed 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) was added K2CO3 (322 mg, 2.34 mmol) and 1H-pyrazole-4-carbonitrile (162 mg, 1.75 mmol). After stirring at 25 °C for 12 h, the mixture was poured into water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column (0-15% EtOAc in PE) to give 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% NH / HO, B = EtOH), flow rate: 50 mL / min) to give 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 min chromatography), 30-90AB_2 MIN_E, 100% purity, C 27 H 40 N3O2[M+H] + MS ESI calculated value 438, found value 438.

[0540] SFC Rt=4.998 min (10 min chromatography), OD_3_EtOH_DEA_5_40_25ML, 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 min 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 min (10 min chromatography), OD_3_EtOH_DEA_5_40_25ML, 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) was added p-toluenesulfonic acid (20 mg, 0.116 mmol) and pyridin-2-ylmethanamine (1.55 g, 14.4 mmol) at 25 °C. The reaction mixture was heated to 130 °C in a Dean-Stark apparatus for 16 h. The reaction was cooled to 25 °C and diluted with EtOAc (30 mL). The organic layer was washed sequentially with saturated NH4Cl (2 × 20 mL), saturated NaHCO3 (20 mL), brine (20 mL), dried over Na2SO4, and then concentrated in vacuo to give crude product P2 (3 g, crude) as a yellow oil, which was Used directly for:

[0547] Step 2. P2 (1 g, 2.53 mmol), Cu(OTf)2 (1.18 g, 3.28 mmol), and the sodium salt of L-ascorbic acid (1 g, 5.06 mmol) were added to a round-bottom flask under N2. Acetone (dry, 8 mL) and MeOH (dry, 8 mL) were added at 25 °C and stirred for 5 min (the reaction mixture may turn brown). O2 from a balloon was bubbled through the reaction mixture for 5 min (a blue / green solution was obtained). The reaction was then heated to 50 °C under an O2 atmosphere for 1.5 h. The reaction mixture was then cooled to 25 °C, and EtOAc (30 mL) and saturated Na4EDTA (30 mL, pH 10) were added, and the reaction mixture was stirred for 1 h. The layers were separated. The aqueous layer was extracted with EtOAc (2 × 30 mL), dried over NaSO, and concentrated in vacuo to give the crude product, which was purified by silica gel column (PE / EtOAc = 3 / 1) to give P3 (230 mg, 28%) as a solid, which was triturated with MeCN (5 mL) at 25 °C to give 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. To the over-dried bottom, t-BuOH (2 mL) and t-BuOK (348 mg, 3.11 mmol) were added. The mixture was degassed and filled 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 eluting with (petroleum ether / ethyl acetate=4 / 1) to give compound 40 (60 mg, 58% yield) as a pale solid, which was triturated with MeCN (2 mL) to give 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 min chromatography), 30-90AB, 100% purity, C 21 H 30 N[M+H-2H2O] + MS ESI calculated value 296, found value 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) was added KOH (632 mg, 11.3 mmol) and MeSO (966 mg, 0.725 mL, 7.66 mol) at 0 °C. The mixture was then warmed to 25 °C and stirred at the same temperature for 16 h. The mixture was quenched by the addition of 50 mL of water and extracted with EtOAc (2 × 30 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column (PE / EtOAc = 10 / 1 to 5:1) to give 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. To the over-dried bottom, t-BuOH (2 mL) and t-BuOK (334 mg, 2.98 mmol) were added. This was evaporated and filled 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. It 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 eluting with (petroleum ether:ethyl acetate=4 / 1) to give compound 41 (25 mg, impure) as a pale yellow oil, which was triturated with MeCN (1 mL) to give 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 min chromatography), 30-90AB, 100% purity, C 22 H 32 N[M+H-2H2O] + MS ESI calculated value 296, found value 296.

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

[0560] Step 1. To a solution of P3 (200 mg, 0.624 mmol) in MeOH (5 mL) was added NaBH4 (46.9 mg, 1.24 mmol) at 25 °C. The reaction was stirred at 25 °C for 30 min. The reaction was quenched with water (10 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to afford 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) was added KOH (211 mg, 3.77 mmol) and MeSO (320 mg, 0.24 mL, 2.54 mmol) at 0 °C. The mixture was then warmed to 25 °C and stirred at the same temperature for 16 h. The mixture was quenched by adding 50 mL of water and extracted with EtOAc (2 × 30 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column (PE / EtOAc = 10 / 1 to 5:1) to give compound 42 (30 mg, 14%) as a solid, which was triturated with n-hexane (3 mL) at 25 °C to give 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 min chromatography), 30-90AB, purity 99%, C 22 H 38 O3Na + [M+Na] + MS ESI calculated value 373, found value 373.

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

[0565] Step 1. To a suspension of EtPPhBr (3.32 g, 8.95 mmol) in THF (40 mL) was added t-BuOK (1 g, 8.95 mmol) at 25 °C under N. After stirring at 60 °C for 30 min, a solution of Q1 (600 mg, 1.79 mmol) in THF (10 mL) was added at 60 °C. The mixture was stirred at 60 °C for 16 h. The mixture was quenched with NH Cl (80 mL). The organic layer was separated, dried over Na SO , filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column (PE / EtOAc = 10 / 1 to 5 / 1) to give 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) was added 9-BBN dimer (597 mg, 2.45 mmol) at 0 °C under N2. The solution was stirred at 60 °C for 16 h. After cooling to 0 °C, a solution of EtOH (15 mL) and NaOH (1.96 mL, 5 M, 9.81 mmol) was added very slowly. After the addition, H2O2 (0.981 mL, 9.81 mmol, 30% in water) was added slowly to maintain the internal temperature below 10 °C. The mixture was stirred at 60 °C under N2 for 1 h. The mixture was cooled again to 30 °C. Water washed (100 mL) was added to the solution. The resulting mixture was added to HCl and extracted with EtOAc (2×50 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo to give 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) was added PCC (413 mg, 1.92 mmol) and silica gel (454 mg) at 25 °C. The solution was then stirred at 25 °C for 3 h. The reaction mixture was filtered, and the residue was washed with anhydrous DCM (2 × 30 mL). The combined filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel column (PE / EtOAc = 8 / 1 to 4 / 1) to give compound 43 (270 mg, impure) as a pale solid. The solid was triturated with MeCN (5 mL) at 25 °C to give compound 45 (10 mg, 4%) as a delivered solid and compound 43 (250 mg, crude) as a pale yellow oil.

[0569] 1H NMR (400MHz, CDCl3) δ 3.33 (s, 3H), 3.08-3.03 (m, 1H), 2.71-2.66 (m, 1H), 2.21 (s, 3H), 2.17-1.97 (m, 2H), 1.58-1.55 (m, 3H), 1.54-1.21 (m, 12H), 1.20-1.00 (m, 5H), 0.98-0.75 (m, 5H), 0.65 (s, 3H).

[0570] LCMS Rt=0.960 min (2 min chromatography), 30-90AB, 100% purity, C 23 H 39 O3 [M+H] + MS ESI calculated value 363, measured value 363.

[0571] Example 26. Synthesis of compound 44. [ka]

[0572] Step 1. To a solution of compound 43 (1 g, 2.75 mmol) in MeOH (15 ml), HBr (44.5 mg, 0.55 mmol, 40% in water) and Br (439 mg, 0.140 mmol) were added at 25 °C. The mixture was stirred at 25 °C for 16 hours. The mixture was quenched with saturated aqueous NaHCO (10 mL), treated with water (20 mL), and extracted with EtOAc (2 × 20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give T1 (1.3 g, crude) as a pale yellow oil, which was used directly for the next step.

[0573] Step 2. To a mixture of T1 (300 mg, 0.680 mmol) and K2CO3 (186 mg, 1.35 mmol) in acetone (5 mL) was added 1H-pyrazole-4-carbonitrile (94 mg, 1.01 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the crude product, which was purified by silica gel column (PE / EtOAc = 2 / 1) to give compound 44 (37 mg, 12%) as a solid.

[0574] 1 H NMR (400MHz, CDCl3) δ 7.80 (s, 2H), 5.45 (d, J=17.8 Hz, 1H), 4.93 (d, J=17.8 Hz, 1H), 3.38 (s, 3H), 3.19-3.14 (m, 1H), 2.73-2.67 (m, 1H), 2.20-2.02 (m, 2H), 1.80-1.65 (m, 3H), 1.50-1.32 (m, 5H), 1.31-1.11 (m, 11H), 1.00-0.80 (m, 3H), 0.77 (s, 3H), 0.66 (s, 3H)

[0575] LCMS Rt=1.113 min (2 min chromatography), 30-90AB, 100% purity, C 27 H 39 N3O3Na + [M+Na] + MS ESI calculated value 476, found value 476.

[0576] Example 27. Synthesis of compounds 45 and 46. [ka]

[0577] Step 1. To a suspension of EtPPhBr (11.5 g, 31.2 mmol) in THF (50 mL) was added t-BuOK (3.50 g, 31.2 mmol) at 25 °C under N. After stirring at 60 °C for 30 min, a solution of P (2 g, 6.24 mmol) in THF (20 mL) was added at 60 °C. The mixture was stirred at 60 °C for 16 h and quenched with NH Cl (100 mL). The organic layer was separated, dried over Na SO , filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column (PE / EtOAc = 10 / 1 to 5 / 1) to give U1 (1.8 g, 87%) as a solid.

[0578] 1 H NMR (400MHz, CDCl3) δ 5.18-5.14 (m, 1H), 3.68-3.63 (m, 1H), 2.47-2.35 (m, 1H), 2.21-2.09 (m, 1H), 1.89-1.70 (m, 5H), 1.69-1.59 (m, 1H), 1.51-1.45 (m, 4H), 1.41-1.19 (m, 8H), 1.16 (s, 3H), 1.12-0.88 (m, 2H), 1.12-0.88 (m, 1H), 1.12-0.88 (m, 1H), 0.86 (s, 3H), 0.84-0.81 (m, 1H), 0.80 (s, 3H).

[0579] Step 2. To a solution of U1 (1.8 g, 5.41 mmol) in DCM (40 mL) was added TBSCl (1.22 g, 8.11 mmol) and 1H-imidazole (735 mg, 10.8 mmol) at 25 °C. The reaction was stirred at 50 °C for 16 h, quenched with water (30 mL), and extracted with DCM (2 × 20 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel column (PE / EtOAc = 10 / 1 to 5 / 1) to give U2 (1.6 g, 66%) as a solid.

[0580] Step 3. To a solution of U2 (1.6 g, 3.58 mmol) in THF (40 mL) was added 9-BBN dimer (4.36 g, 17.9 mmol) at 0 °C under N2. The solution was stirred at 60 °C for 16 h. After cooling to 0 °C, a solution of EtOH (40 mL) and NaOH (7.15 mL, 5 M, 35.8 mmol) was added very slowly. After the addition, HO2 (3.56 ml, 35.8 mmol, 30% in water) was added slowly to maintain the internal temperature below 10 °C. The mixture was stirred at 60 °C under N2 for 1 h. The mixture was recooled to 30 °C, treated with water (100 mL), and extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give U3 (2.3 g, crude) as a colorless oil, which was used directly for the next step.

[0581] 1 H NMR (400MHz, CDCl3) δ 4.15-4.06 (m, 1H), 3.40-3.30 (m, 1H), 1.76-1.68 (m, 3H), 1.56-1.43 (m, 6H), 1.40-1.30 (m, 4H), 1.29-1.15 (m, 13H), 1.04-0.80 (m, 4H), 0.78-0.73 (m, 6H).

[0582] Step 4. To a solution of U3 (300 mg, 1.72 mmol) in DCM (15 mL) was added silica gel (404 mg) and PCC (368 mg, 1.71 mmol) at 25° C. The reaction was stirred at 25° C. for 1 h. The mixture was filtered, and the filtrate was concentrated in vacuo to give the crude product, which was purified by silica gel column (PE / EtOAc=6 / 1 to 2 / 1) to give compound 46 (10 mg, 3%) and compound 45 (10 mg, 3%) as solids.

[0583] Compound 45: 1 H NMR (400MHz, CDCl3) δ 4.86 (s, 1H), 3.45-3.40 (m, 1H), 2.50-2.34 (m, 1H), 2.21-2.05 (m, 4H), 2.03-1.89 (m, 1H), 1.88-1.63 (m, 3H), 1.48-1.22 (m, 9H), 1.21-1.12 (m, 6H), 1.11-0.98 (m, 1H), 0.97-0.80 (m, 3H), 0.75-0.70 (m, 6H).

[0584] LCMS Rt=0.969 min (2 min chromatography), 30-90AB, 100% purity, C 22 H 35 O2 [M+H-H2O] + MS ESI calculated value 331, found value 331.

[0585] Compound 46: 1 H NMR (400MHz, CDCl3) δ 3.35-3.10 (m, 1H), 2.54-2.38 (m, 1H), 2.34-2.09 (m, 5H), 1.89-1.62 (m, 4H), 1.60-1.53 ​​(m, 2H), 1.47-1.24 (m, 9H), 1.21-1.12 (m, 4H), 1.09 (s, 1H), 1.03-0.89 (m, 4H), 0.83 (s, 3H).

[0586] LCMS Rt=0.977 min (2 min chromatography), 30-90AB, 100% purity, C 22 H 35 O3 [M+H] + MS ESI calculated value 347, found value 347.

[0587] Example 28. Synthesis of Compound 47. [ka]

[0588] Step 1. To a solution of compound 45 (560 mg, 1.60 mmol) in MeOH (15 ml) was added HBr (25.9 mg, 0.32 mmol, 40% in water) and Br (255 mg, 1.60 mmol) at 25 °C. The mixture was stirred at 25 °C for 16 h. The mixture was quenched with saturated aqueous NaHCO (10 mL), treated with water (20 mL), and extracted with EtOAc (2 × 20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give V1 (700 mg, crude) as a pale yellow oil, which was used directly for the next step.

[0589] Step 2. To a mixture of V1 (150 mg, 0.351 mmol) and K2CO3 (96.9 mg, 0.702 mmol) in acetone (5 mL) was added 1H-pyrazole-4-carbonitrile (48.9 mg, 0.526 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product (50 mg), which was triturated with MeCN (5 mL) to give compound 47 (41 mg, 27%) as a solid.

[0590] 1 H NMR (400MHz, DMSO-d6) δ 8.31 (s, 1H), 8.05 (s, 1H), 5.87 (d, J= 18.2 Hz, 1H), 5.22 (d, J= 18.2 Hz, 1H), 4.92-4.88 (m, 1H), 3.88 (s, 1H), 3.56-3.49 (m, 1H), 2.86-2.76 (m, 1H), 1.96-1.92 (m, 1H), 1.73-1.58 (m, 4H), 1.57-1.44 (m, 1H), 1.42-1.22 (m, 7H), 1.19-1.11 (m, 5H), 1.07 (s, 3H), 0.92-0.77 (m, 2H), 0.70 (s, 3H), 0.54 (s, 3H)

[0591] LCMS Rt=0.980 min (2 min chromatography), 30-90AB, 100% purity, C 26 H 37 N3O3Na + [M+Na] + MS ESI calculated value 462, found value 462.

[0592] Example 29. Synthesis of Compound 48. [ka]

[0593] To a solution of compound 47 (50 mg, 0.114 mmol) in DCM (10 mL) was added PCC (98.0 mg, 0.455 mmol) and silica gel (150 mg) at 25° C. The solution was then stirred at 25° C. for 5 h. The reaction mixture was filtered, and the residue was washed with anhydrous DCM (2×30 mL). The combined filtrate was concentrated in vacuo to give the crude product, which was purified by silica gel column (PE / EtOAc=1 / 1) to give compound 48 (13 mg, 26%) as a solid.

[0594] 1 H NMR (400MHz, CDCl3) δ 7.83-7.79 (m, 2H), 5.55 (d, J = 18.4 Hz, 1H), 5.08 (d, J = 18.4 Hz, 1H), 3.27 (t, J = 9.0 Hz, 1H), 2.52-2.39 (m, 1H), 2.39-2.29 (m, 1H), 2.26-2.14 (m, 1H), 1.89-1.68 (m, 3H), 1.58-1.43 (m, 4H), 1.40-1.23 (m, 9H), 1.21 (s, 3H), 1.07-0.99 (m, 1H), 1.07-0.99 (m, 1H), 0.96 (s, 3H), 0.84 (s, 3H).

[0595] LCMS Rt=0.983 min (2 min chromatography), 30-90AB, 100% purity, C 26H 36 N3O3[M+H] + MS ESI calculated value 438, found value 438.

[0596] Example 30. Synthesis of compounds 49 and 50. [ka]

[0597] To a mixture of V1 (400 mg, 0.936 mmol) and K2CO3 (258 mg, 1.87 mmol) in acetone (5 mL) was added 1H-pyrazole-4-carbonitrile (166 mg, 1.40 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by preparative HPLC (column: Boston Green ODS 150 × 30 5 u, gradient: 34–44% B (A = 0.1% TFA-ACN, B = acetonitrile), flow rate: 30 mL / min) to give a mixture of compound 49 and compound 50 (120 mg, crude) as a yellow oil. This oil was purified by SFC (column: OD (250 mm × 30 mm, 5 μm); mobile phase: supercritical CO / MeOH + NHH0 = 40 / 40; flow rate: 50 ml / min; wavelength: 220 nm) to give compound 49 (20 mg, 17%) as a solid and compound 50 (50 mg, 42%) as a solid.

[0598] Compound 49: 1 H NMR (400MHz, CDCl3) δ 9.28 (s, 1H), 8.17 (d, J = 5.6 Hz, 1H), 7.99 (s, 1H), 7.52 (d, J = 5.6 Hz, 1H), 5.81 (d, J = 17.6 Hz, 1H), 5.37 (d, J = 17.6 Hz, 1H), 3.61-3.56 (m, 1H), 2.66-2.60 (m, 2H), 2.21-2.08 (m, 1H), 1.92-1.64 (m, 4H), 1.54-1.44 (m, 4H), 1.42-1.31 (m, 4H), 1.30-1.25 (m, 3H), 1.21 (s, 3H), 1.18-1.05 (m, 3H), 0.97-0.85 (m, 2H), 0.77 (s, 3H), 0.73 (s, 3H).

[0599] LCMS Rt=0.655 minutes (2 minutes of のクロマトグラフィー), 30-90AB, purity 100%, C 28 H 40 N3O3[M+H] + The MS ESI calculated value is 466 and the measured value is 466.

[0600] Compound 50: 1 H NMR (400MHz, CDCl3) δ ...

Claims

[Claim 1] Brain excitability.

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