C17, C20, and C21 substituted neurostimulant steroids and methods of their use

Abstract

To provide C17, C20, and C21 substituted neurostimulant steroids and methods for their use. [Solution] Described herein are neurostimulatory steroids or pharmaceutically acceptable salts thereof. Such compounds are expected to act as GABA modulators in certain embodiments. Pharmaceutical compositions containing the compounds described herein are also provided, as well as methods of use and treatment, such as for inducing sedation and / or anesthesia. In one aspect, provided herein are methods for treating epilepsy or status epilepticus in a subject.

Description

[Technical Field]

[0001] Citation of Related Applications This application claims priority to U.S. Application No. 62 / 360,813, filed July 11, 2016, and U.S. Application No. 62 / 360,847, filed July 11, 2016, and U.S. Application No. 62 / 424,803, filed November 18, 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). 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]

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

[0007] 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.

[0008] In one aspect, the compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein in formula (I), R 2 , R 4 , R 6 , R 7 , 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 ,-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 with the carbon atom to which they are attached form a carbocyclyl, heterocyclyl, or -C(=O)-; R 3 is alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; R 17a and R 17b 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 , -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 where R17a and R 17b At least one of them is not hydrogen く;R 19 is hydrogen or alkyl (e.g., unsubstituted alkyl or substituted alkyl (e.g., —C(R C )2OR A1 where R C is hydrogen or alkyl; R 5 is absent or is hydrogen; [ka] represents a single or double bond, where one [ka] is a double bond, the other [ka] is a single bond, and R 5 does not exist.

[0009] In some embodiments, R 19 is hydrogen or alkyl. In some embodiments, R 19 is unsubstituted alkyl. In some embodiments, R 19 is substituted alkyl. In some embodiments, R 19 is -CH2OH, -CH2OCH3, -CH2OCH2CH3, or -CH2OCH(CH3)2.

[0010] In some embodiments, R 2 is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , or -N(R A1 )2. In some embodiments, R 2 is hydrogen, halogen, alkyl, or -OR A1 In some embodiments, R 2is hydrogen.

[0011] In some embodiments, R 3 is alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, R 3 is alkyl (e.g., substituted or unsubstituted alkyl). In some embodiments, R 3 is methyl and ethyl (e.g., substituted or unsubstituted alkyl).

[0012] In some embodiments, R 4 is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , or -N(R A1 )2. In some embodiments, R 4 is hydrogen, halogen, alkyl, or -OR A1 In some embodiments, R 4 is hydrogen.

[0013] In some embodiments, [ka] represents a single bond, and R 5 is hydrogen. In some embodiments, R 5 does not exist, [ka] represents a single or double bond, where one [ka] is a double bond, the other [ka] is a single bond.

[0014] In some embodiments, R 6 is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , or -N(R A1 )2. In some embodiments, R 6 is hydrogen, halogen, alkyl, or -OR A1 In some embodiments, R 6 is hydrogen.

[0015] In some embodiments, R 7 is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , or -N(R A1 )2. In some embodiments, R 7 is hydrogen, halogen, alkyl, or -OR A1 In some embodiments, R 7 is hydrogen.

[0016] In some embodiments, R 11a is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2 or R 11a and R 11b together with the carbon atom to which they are attached form -C(=O)-. In some embodiments, R 11a is hydrogen, halogen, alkyl, or -OR A1 In some embodiments, R 11a and R 11b together with the carbon atom to which they are attached form -C(=O)-. In some embodiments, R 11a and R 11b is hydrogen.

[0017] In some embodiments, R 2 , R 4 , R 6 , R 7 , R 11a , and R 11b each independently represents hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , or -N(R A1 )2. In some embodiments, R 2 , R 4 , R 6 , R 7 , R 11a , and R 11b each independently represents hydrogen, halogen, alkyl, or -OR A1 In some embodiments, R 2 , R 4 , R 6 , R 7 , R 11a , and R 11b is hydrogen.

[0018] In some embodiments, R 17a and R 17b each independently represents hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, -SR A1 , -N(R A1 )2, -NHC(=O)R A1 -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 where R 17a and R 17b In some embodiments, at least one of R 17a and R 17b each independently represents hydrogen, halogen, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, -SR A1 , -N(R A1 )2, -NHC(=O)R A1 -S(=O)R A2 , -SO2RA2 , or -S(=O)2OR A1 where R 17a and R 17b At least one of the is not hydrogen.

[0019] In some embodiments, R 17a is halogen, cyano, nitro, alkyl, carbocyclyl, heterocyclyl, -OR A1 , -SR A1 , -N(R A1 )2, -NHC(=O)R A1 , -S(=O)R A2 , or -SO2R A2 In some embodiments, R 17a is halogen, nitro, alkyl, carbocyclyl, heterocyclyl, -OR A1 , -SR A1 , -N(R A1 )2, -NHC(=O)R A1 , -S(=O)R A2 , or -SO2R A2 In some embodiments, R 17a is halogen, cyano, nitro, alkyl, -OR A1 , -SR A1 , or -N(R A1 )2.

[0020] In one aspect, the compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein in formula (II), R 2 , R 4 , R 6 , R 7 , 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 with the carbon atom to which they are attached form a carbocyclyl, heterocyclyl, or -C(=O)- group; R 3 is hydrogen, alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; A is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, -OR A1 , -SR A1 , or -N(R A1 )2;R 19 is hydrogen or alkyl (e.g., unsubstituted alkyl (e.g., —CH) or substituted alkyl (e.g., —C(R C )2OR A1 where R C is hydrogen or alkyl; R 5 is absent or is hydrogen; [ka] represents a single or double bond, where one [ka] is a double bond, the other [ka] is a single bond, and R 5 does not exist.

[0021] In some embodiments, A is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, or -OR A1 is.

[0022] In some embodiments, R 19 is hydrogen. In some embodiments, R 19 is alkyl (e.g., substituted or unsubstituted alkyl). In some embodiments, R 19 is -CH3 or -CH2CH3. In some embodiments, R 19 is -C(R C )2OR A1 In some embodiments, R 19 is -CH2OH, -CH2OCH3, -CH2OCH2CH3, or -CH2OCH(CH3)2.

[0023] In some embodiments, R 2 is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , or -N(R A1 )2. In some embodiments, R 2 is hydrogen, halogen, alkyl, or or A1 In some embodiments, R 2 is hydrogen.

[0024] In some embodiments, R 3 is alkyl (e.g., substituted or unsubstituted alkyl). In some embodiments, R 3 is methyl and ethyl (eg, substituted or unsubstituted methyl, substituted or unsubstituted ethyl).

[0025] In some embodiments, R 4 is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , or -N(R A1 )2. In some embodiments, R 4 is hydrogen, halogen, alkyl, or -OR A1 In some embodiments, R 4 is hydrogen.

[0026] In some embodiments, [ka] represents a single bond, and R 5 is hydrogen. In some embodiments, R 5 does not exist, [ka] represents a single or double bond, where one [ka] is a double bond, the other [ka] is a single bond.

[0027] In some embodiments, R 6 is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , or -N(R A1 )2. In some embodiments, R 6 is hydrogen, halogen, alkyl, or -OR A1 In some embodiments, R 6 is hydrogen.

[0028] In some embodiments, R7 is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , or -N(R A1 )2. In some embodiments, R 7 is hydrogen, halogen, alkyl, or -OR A1 In some embodiments, R 7 is hydrogen.

[0029] In some embodiments, R 11a is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2 or R 11a and R 11b together with the carbon atom to which they are attached form -C(=O)-. In some embodiments, R 11a is hydrogen, halogen, alkyl, or -OR A1 In some embodiments, R 11a and R 11b together with the carbon atom to which they are attached form -C(=O)-. In some embodiments, R 11a and R 11b is hydrogen.

[0030] In some embodiments, R 2 , R 4 , R 6 , R 7 , R 11a , and R 11b each independently represents hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , or -N(R A1 )2. In some embodiments, R 2 , R 4 , R 6 , R 7 , R 11a , and R11b Each of is hydrogen, halogen, alkyl, or -OR A1 In some embodiments, R 2 , R 4 , R 6 , R 7 , R 11a , and R 11b Each of is hydrogen.

[0031] In some embodiments, the compound of Formula (II) has the formula (II-a) or (II-b): [ka] is a compound of

[0032] In some embodiments, the compound of formula (II) has the formula (II-c): [ka] In the formula (II-c), R 21a and R 21b 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 or R 21a and R 21b together with the carbon atom to which they are attached form a carbocyclyl, heterocyclyl, or -C(=O)- group; Q is hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , or -N(R A1) 2; and n is an integer selected from 1, 2, and 3.

[0033] In some embodiments, the compound of Formula (II) has the formula (II-d): [ka] is a compound of

[0034] In one aspect, the compound of formula (III): [ka] or a pharmaceutically acceptable salt thereof, wherein in formula (III), R 2 , R 4 , R 6 , R 7 , 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 11btogether with the carbon atom to which they are attached form a carbocyclyl, heterocyclyl, or -C(=O)- group; Q is hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, -OR A1 , -SR A1 , or -N(R A1 )2;R 19 is unsubstituted alkyl; R 5 is absent or is hydrogen; [ka] represents a single or double bond, where one [ka] is a double bond, the other [ka] is a single bond, and R 5 does not exist.

[0035] In one aspect, the compound of formula (IV): [ka] or a pharmaceutically acceptable salt thereof, wherein in formula (IV), R 2 , R 4 , R 6 , R 7 , 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, hetero aryl, 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 with the carbon atom to which they are attached form a carbocyclyl, heterocyclyl, or -C(=O)- group; R 3 is alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; Q is halogen, cyano, nitro, heterocyclyl linked via a C atom, aryl, heteroaryl linked via a C atom, -O-alkenyl, -O-alkynyl, -SR A1 , -N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 , -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 and;R 19 is -C(R C )2OR A1 where R C is hydrogen or alkyl; R 5 is absent or is hydrogen; [ka] represents a single or double bond, where one [ka] is a double bond, the other [ka] is a single bond, and R5 does not exist.

[0036] In one aspect, the compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein in formula (I), R 2 , R 4 , R 6 , R 7 , 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 ,-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 with the carbon atom to which they are attached form a carbocyclyl, heterocyclyl, or -C(=O)-; R 3 is hydrogen, alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; R 17a and R 17b each independently represents hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -ORA1 , -SR A1 , -N(R A1 )2, -NHC(=O)R A1 , -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 where R 17a and R 17b At least one of R is not hydrogen; 19 is hydrogen or alkyl (e.g., unsubstituted or substituted alkyl (e.g., -C(R C )2OR A1 where R C is hydrogen or alkyl; R 5 is absent or is hydrogen; [ka] represents a single or double bond, where one [ka] is a double bond, the other [ka] is a single bond, and R 5 does not exist.

[0037] In some embodiments, R 19 is hydrogen or alkyl. In some embodiments, R 19 is unsubstituted alkyl. In some embodiments, R 19 is substituted alkyl. In some embodiments, R 19 is -CH2OH, -CH2OCH3, -CH2OCH2CH3, or -CH2OCH(CH3)2.

[0038] In some embodiments, R 2 is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -ORA1 , -SR A1 , or -N(R A1 )2. In some embodiments, R 2 is hydrogen, halogen, alkyl, or -OR A1 In some embodiments, R 2 is hydrogen.

[0039] In some embodiments, R 3 is alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, R 3 is alkyl (e.g., substituted or unsubstituted alkyl), alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, R 3 is methyl and ethyl (e.g., substituted or unsubstituted alkyl).

[0040] In some embodiments, R 4 is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , or -N(R A1 )2. In some embodiments, R 4 is hydrogen, halogen, alkyl, or -OR A1 In some embodiments, R 4 is hydrogen.

[0041] In some embodiments, [ka] represents a single bond, and R 5 is hydrogen. In some embodiments, R 5 does not exist, [ka] represents a single or double bond, where one [ka] is a double bond, the other [ka] is a single bond.

[0042] In some embodiments, R 6 is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , or -N(R A1 )2. In some embodiments, R 6 is hydrogen, halogen, alkyl, or -OR A1 In some embodiments, R 6 is hydrogen.

[0043] In some embodiments, R 7 is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , or -N(R A1 )2. In some embodiments, R 7 is hydrogen, halogen, alkyl, or -OR A1 In some embodiments, R 7 is hydrogen.

[0044] In some embodiments, R 11a is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2 or R 11a and R 11b together with the carbon atom to which they are attached form -C(=O)-. In some embodiments, R 11a is hydrogen, halogen, alkyl, or -OR A1In some embodiments, R 11a and R 11b together with the carbon atom to which they are attached form -C(=O)-. In some embodiments, R 11a and R 11b is hydrogen.

[0045] In some embodiments, R 2 , R 4 , R 6 , R 7 , R 11a , and R 11b each independently represents hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , or -N(R A1 )2. In some embodiments, R 2 , R 4 , R 6 , R 7 , R 11a , and R 11b each independently represents hydrogen, halogen, alkyl, or -OR A1 In some embodiments, R 2 , R 4 , R 6 , R 7 , R 11a , and R 11b is hydrogen.

[0046] In some embodiments, R 17a and R 17b each independently represents hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, -SR A1 , -N(R A1 )2, -NHC(=O)R A1 -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 where R 17a and R 17b In some embodiments, at least one of R17a and R 17b each independently represents hydrogen, halogen, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, -SR A1 , -N(R A1 )2, -NHC(=O)R A1 -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 where R 17a and R 17b At least one of the is not hydrogen.

[0047] In some embodiments, R 17a is halogen, cyano, nitro, alkyl, carbocyclyl, heterocyclyl, -OR A1 , -SR A1 , -N(R A1 )2, -NHC(=O)R A1 , -S(=O)R A2 , or -SO2R A2 In some embodiments, R 17a is halogen, nitro, alkyl, carbocyclyl, heterocyclyl, -OR A1 , -SR A1 , -N(R A1 )2, -NHC(=O)R A1 , -S(=O)R A2 , or -SO2R A2 In some embodiments, R 17a is halogen, cyano, nitro, alkyl, -OR A1 , -SR A1 , or -N(R A1 )2.

[0048] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0049] In one aspect, the compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein in formula (II), R 2 , R 4 , R 6 , R 7 , 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 with the carbon atom to which they are attached form a carbocyclyl, heterocyclyl, or -C(=O)- group; R 3 is hydrogen, alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; A is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, -OR A1 , -SR A1 , or -N(R A1 )2;R 19 is hydrogen or alkyl (e.g., unsubstituted alkyl (e.g., —CH) or substituted alkyl (e.g., —C(R C)2OR A1 where R C is hydrogen or alkyl; R 5 is absent or is hydrogen;

[0050] [ka] represents a single or double bond, where one [ka] is a double bond, the other [ka] is a single bond, and R 5 does not exist.

[0051] In some embodiments, A is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, or -OR A1 is.

[0052] In some embodiments, R 19 is hydrogen. In some embodiments, R 19 is alkyl (e.g., substituted or unsubstituted alkyl). In some embodiments, R 19 is -CH3 or -CH2CH3. In some embodiments, R 19 is -C(R C )2OR A1 In some embodiments, R 19 is -CH2OH, -CH2OCH3, -CH2OCH2CH3, or -CH2OCH(CH3)2.

[0053] In some embodiments, R 2 is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , or -N(R A1)2. In some embodiments, R 2 is hydrogen, halogen, alkyl, or -OR A1 In some embodiments, R 2 is hydrogen.

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

[0055] In some embodiments, R 4 is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , or -N(R A1 )2. In some embodiments, R 4 is hydrogen, halogen, alkyl, or -OR A1 In some embodiments, R 4 is hydrogen.

[0056] In some embodiments, [ka] represents a single bond, and R 5 is hydrogen. In some embodiments, R 5 does not exist, [ka] represents a single or double bond, where one [ka] is a double bond, the other [ka] is a single bond.

[0057] In some embodiments, R 6 is hydrogen, halogen, alkyl, carbocyclyl, Heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , or -N(R A1 )2. In some embodiments, R 6 is hydrogen, halogen, alkyl, or -OR A1 In some embodiments, R 6 is hydrogen.

[0058] In some embodiments, R 7 is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , or -N(R A1 )2. In some embodiments, R 7 is hydrogen, halogen, alkyl, or -OR A1 In some embodiments, R 7 is hydrogen.

[0059] In some embodiments, R 11a is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2 or R 11a and R 11b together with the carbon atom to which they are attached form -C(=O)-. In some embodiments, R 11a is hydrogen, halogen, alkyl, or -OR A1 In some embodiments, R 11a and R 11b together with the carbon atom to which they are attached form -C(=O)-. In some embodiments, R 11a and R 11b is hydrogen.

[0060] In some embodiments, R 2 , R 4 , R 6 , R 7 , R 11a , and R 11b each independently represents hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , or -N(R A1 )2. In some embodiments, R 2 , R 4 , R 6 , R 7 , R 11a , and R 11b Each of is hydrogen, halogen, alkyl, or -OR A1 In some embodiments, R 2 , R 4 , R 6 , R 7 , R 11a , and R 11b Each of is hydrogen.

[0061] In some embodiments, the compound of Formula (II) has the formula (II-a) or (II-b): [ka] is a compound of

[0062] In some embodiments, the compound of Formula (I) has the formula (II-c): [ka] In the formula (II-c), R 21a and R 21b 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 or R 21a and R 21b together with the carbon atom to which they are attached form a carbocyclyl, heterocyclyl, or -C(=O)- group; Q is hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , or -N(R A1 ) 2; and n is an integer selected from 1, 2, and 3.

[0063] In some embodiments, the compound of Formula (II) has the formula (II-d): [ka] is a compound of

[0064] In one aspect, the compound of formula (III-a): [ka] or a pharmaceutically acceptable salt thereof, wherein in formula (III-a), R 2 , R 4 , R 6 , R 7 , 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 RA1 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 with the carbon atom to which they are attached form a carbocyclyl, heterocyclyl, or -C(=O)- group; Q is hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, -OR A1 , -SR A1 , or -N(R A1 )2;R 19 is unsubstituted alkyl; R 5 is absent or is hydrogen; [ka] represents a single or double bond, where one [ka] is a double bond, the other [ka] is a single bond, and R 5 does not exist.

[0065] In one aspect, the compound of formula (III-b): [ka] or a pharmaceutically acceptable salt thereof, wherein in formula (III-b), R 2 , R 4 , R 6 , R 7 , 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 with the carbon atom to which they are attached form a carbocyclyl, heterocyclyl, or -C(=O)- group; R 3 is alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; Q is halogen, cyano, nitro, heterocyclyl linked via a C atom, aryl, heteroaryl linked via a C atom, -O-alkenyl, -O-alkynyl, -SR A1 , -N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 , -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 and;R 19 is -C(R C )2OR A1 where R C is hydrogen or alkyl; R 5is absent or is hydrogen; [ka] represents a single or double bond, where one [ka] is a double bond, the other [ka] is a single bond, and R 5 does not exist.

[0066] In one aspect, the compound of formula (1-A): [ka] or a pharmaceutically acceptable salt thereof, wherein in formula (1-A), R 3 is alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; R X and R Y each is independently hydrogen, aryl, or alkyl; R X and R Y are bonded together to form a 3- to 10-membered heterocyclic ring; R 19 is hydrogen or alkyl (e.g., unsubstituted alkyl or substituted alkyl (e.g., —C(R C )2OR A1 where R C is hydrogen or alkyl; R 5 is absent or is hydrogen; [ka] represents a single or double bond, where one [ka] is a double bond, the other [ka] is a single bond, and R 5 is absent; a is 0 or 1; provided that if and only if a is 0, then R X and R Y are bonded together to form a 3- to 8-membered heterocycle.

[0067] In some embodiments, R X and R Y In some embodiments, R 3 is alkyl. In some embodiments, R 19 is hydrogen.

[0068] In some embodiments, the compound has the formula (1-A-1): [ka] In formula (1-A-1), R Y4 Each instance of is independently alkyl, cyano, or halo; and e is 0, 1, 2, 3, 4, or 5.

[0069] In some embodiments, R Y4 Each instance of is independently hydrogen, —CH, —CN, or —F. In some embodiments, e is 3. In some embodiments, R X is hydrogen. In some embodiments, R Y4 Each instance of is independently hydrogen, —CH, —CN, or —F, and R X is hydrogen and e is 3. In some embodiments, R Y4 Each instance of is independently hydrogen, —CH, —CN, or —F, and R X is hydrogen and e is 2. In some embodiments, e is 1. Y4 is -F. In some embodiments, R Y4is -F and e is 1.

[0070] In some embodiments, the compound has the formula (1-A-2): [ka] is a compound of In some embodiments, R Y4 Each instance of is independently hydrogen, —CH, —CN, or —F. In some embodiments, e is 3. In some embodiments, R X is hydrogen. In some embodiments, R Y4 Each instance of is independently hydrogen, —CH, —CN, or —F, and R X is hydrogen and e is 3. In some embodiments, R Y4 Each instance of is independently hydrogen, —CH, —CN, or —F, and R X is hydrogen and e is 2. In some embodiments, e is 1. In some embodiments, R Y4 is -F.

[0071] In some embodiments, the compound has the formula (1-A-3): [ka] In formula (1-A-3), R Y1 and R Y2 each is independently alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and b=0, 1, 2, 3.

[0072] In some embodiments, R Y1 and R Y2 Not both are -CH(CH3)2.

[0073] In some embodiments, the compound has the formula (1-A-4): [ka] is a compound of In some embodiments, R Y1 is hydrogen, —CH, or —CHCH, —CH(CH), or cycloalkyl. 3 teeth , —CH, —CF, —CHOCH, —CHOCHCH. In some embodiments, R Y2 is heterocyclyl, aryl, or heteroaryl. In some embodiments, R Y2 is aryl substituted with 0-5 -CH3, -CN, -F, -CF3, or a combination thereof, or heteroaryl substituted with 0-5 -CH3, -CN, -F, -CF3.

[0074] In some embodiments, R Y2 is aryl substituted with 0 to 5 -CH3, -CN, -F, or -CF3, or R X is hydrogen, —CH, or —CHCH. In some embodiments, R Y2 is aryl substituted with 0 to 5 -CH3, -CN, -F, or -CF3.

[0075] In some embodiments, the compound has the formula (1-A-5): [ka] In formula (1-A-5), R Y3 Each occurrence of is aryl or heteroaryl, or two R Y3 the groups are joined together to form a 6- to 10-membered ring; c is 0, 1, 2, or 3; and d is 0, 1, 2, or 3.

[0076] In some embodiments, the compound has the formula (1-A-6): [ka] is a compound of

[0077] In some embodiments, when d is 2, two R Y3 The groups are joined together to form an aryl. In some embodiments, R Y2 is aryl substituted with 0-5 -CH, -CN, -F, -CF. In some embodiments, the compound has formula (1-A-7) or formula (1-A-8): [ka] is a compound of

[0078] In some embodiments, R Y2 is aryl substituted with 0 to 5 -CH3, -CN, -F, or -CF3, or R 3 -CH3, -CF3, -CH2OCH 3, -CH2OCH2CH3.

[0079] In one aspect, the formula (2-A) [ka] or a pharmaceutically acceptable salt thereof, wherein in formula (2-A), R 3 is -CH3, -CF3, -CH2OCH3, -CH2OCH2CH3; R 19 is hydrogen, -CH3, or -CH2OR A1 where R A1 is optionally substituted alkyl; R 3 is -CH3, -CF3, -CH2OCH3, -CH2OCH2CH3; R 17a is -NR A2 R A3 , -N(R1)C(O)R A2 , -N(R1)SO2R A2 , -OR A3 , cycloalkyl, heterocyclyl, aryl, or heteroaryl, where R A2 and R A3each independently represents hydrogen, carbocyclyl, heterocyclyl, aryl, heteroaryl, or -OR A4 where R A4 is hydrogen or alkyl; or R 17A teeth, [ka] where A is oxazolyl or thiazolyl; R 17b is hydrogen, hydroxyl, alkyl, or alkoxy; [ka] represents a single or double bond, where one [ka] is a double bond, the other [ka] is a single bond, and R 5 does not exist; However, R 17a is oxazolyl or [ka] If R 17b is not hydrogen or R 17a When is heterocyclyl, R 19 is hydrogen, or R 17a -OR A4 If R 19 is hydrogen, This is subject to the following conditions.

[0080] In some embodiments, R 17a is -NR A2 R A3 , -N(R1)C(O)R A2 , -N(R1)SO2R A2 In some embodiments, R 17ais aryl, heteroaryl, cycloalkyl, or heterocyclyl. In some embodiments, R 19 is hydrogen. In some embodiments, R 17a is heteroaryl. In some embodiments, R 17a is heteroaryl and R 19 is hydrogen. In some embodiments, R 17a is pyridyl , R 19 is hydrogen.

[0081] In one aspect, the formula (3-A) [ka] or a pharmaceutically acceptable salt thereof, wherein in formula (3-A), R 19 is hydrogen or alkyl; R 17a is nitro or alkoxy (e.g., -OCH3); R 2 , R 4 , R 11a , or R 11b each is independently hydrogen, alkyl, or alkoxy, or R 11a and R 11b together to form oxo; [ka] represents a single or double bond, where one [ka] is a double bond, the other [ka] is a single bond, and R 5 does not exist;R 5 is absent or hydrogen as determined by valence; provided that R 2 , R 11a , and R 11bis hydrogen, R 4 is alkyl, or R 4 , R 11a , and R 11b is hydrogen, R 2 is alkyl, or R 4 is hydrogen, R 2 is —OH or alkoxy, and R 11a is hydrogen and R 11b is —OH or alkoxy, or R 2 is —OH or alkoxy, and R 11a and R 11b are taken together to form oxo.

[0082] In some embodiments, R 4 is hydrogen and R 2 is —OH or alkoxy, and R 11a is hydrogen and R 11b is —OH or alkoxy. In some embodiments, R 4 is hydrogen and R 2 is —OH or alkoxy, and R 11a and R 11b taken together form oxo. In some embodiments, R 17a is nitro. In some embodiments, R 17a is alkoxy. In some embodiments, R 17a is methoxy and R 2 is methyl.

[0083] In one aspect, also provided herein are compounds set forth in Table 1, or pharmaceutically acceptable salts thereof.

[0084] In one aspect, provided herein is a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), Formula (1-A), Formula (2-A), or Formula (3-A)) and a pharmaceutically acceptable excipient.

[0085] In one aspect, provided herein is a method of inducing sedation and / or anesthesia in a subject, comprising administering to the subject an effective amount of a compound described herein (e.g., a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), Formula (1-A), Formula (2-B), Formula (3-C), Formula (4-D), Formula (5-E), Formula (6-F), Formula (7-H), Formula (8-I), Formula (9-I), Formula (10-I), Formula (11-I), Formula (12-I), Formula (13-I), Formula (14-I), Formula (15-I), Formula (16-I), Formula (17-I), Formula (18-I), Formula (19-I), Formula (20-I), Formula (21-I), Formula (22-I), Formula (23-I), Formula (24-I), Formula (25-I), Formula (26-I), Formula (27-I), Formula (28-I), A compound of formula (3-A), or a compound of formula (3-A), or a pharmaceutically acceptable salt thereof, is administered to the patient.

[0086] In one aspect, provided herein is a method of administering to a subject in need thereof an effective amount of a compound described herein (e.g., a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), Formula (1-A), Formula (2-A), or Formula (3-A)), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the compound, wherein the subject experiences sedation and / or anesthesia within 2 hours of administration. In some embodiments, the subject experiences sedation and / or anesthesia within 1 hour of administration. In some embodiments, the subject experiences immediate sedation and / or anesthesia. In some embodiments, the compound is administered by intravenous administration. In some embodiments, the compound is administered chronically.

[0087] In some embodiments, the subject is a mammal, hi some embodiments, the subject is a human.

[0088] In some embodiments, the compound is administered in combination with another therapeutic agent.

[0089] 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 (II), Formula (III), or Formula (IV), Formula (1-A), Formula (2-A), or Formula (3-A)).

[0090] 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 (II), Formula (III), or Formula (IV), Formula (1-A), Formula (2-A), or Formula (3-A)).

[0091] 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 (II), Formula (III), or Formula (IV), Formula (1-A), Formula (2-A), or Formula (3-A)).

[0092] 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 (II), Formula (III), or Formula (IV), Formula (1-A), Formula (2-A), or Formula (3-A)).

[0093] 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 (II), Formula (III), or Formula (IV), Formula (1-A), Formula (2-A), or Formula (3-A)).

[0094] 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 (II), Formula (III), or Formula (IV), Formula (1-A), Formula (2-A), or Formula (3-A)).

[0095] In one aspect, provided herein is a method for treating a disorder associated with GABA function in a subject in need thereof, the method comprising: The method includes administering to the subject a therapeutically effective amount of a compound described herein (e.g., a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), Formula (1-A), Formula (2-A), or Formula (3-A)), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the compound.

[0096] 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 (II), Formula (III), or Formula (IV), Formula (1-A), Formula (2-A), or Formula (3-A)) and a sterile diluent.

[0097] 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), Formula (II), Formula (III), or Formula (IV), Formula (1-A), Formula (2-A), or Formula (3-A)). 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.

[0098] In some embodiments, the subject has Rett syndrome, Fragile X syndrome, or Angelman syndrome. In an embodiment of the present invention, for example, the following items are provided: (Item 1) Formula (1-A): [ka] or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (1-A): R 3 is alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; R X and R Y each is independently hydrogen, aryl, or alkyl, or R X and R Y are joined together to form a 3- to 10-membered heterocycle; R 19 is hydrogen or alkyl; R 5 is absent or is hydrogen; [ka] represents a single or double bond, where one [ka] is a double bond, the other [ka] is a single bond, and R 5 does not exist; a is 0 or 1; However, only when a is 0, R X and R Y or a pharmaceutically acceptable salt thereof, provided that: (Item 2) The compound has the formula (1-A-1) [ka] The compound according to item 1, wherein in formula (1-A-1), R Y4 each instance of is independently alkyl, cyano, or halo; The compound wherein e is 0, 1, 2, 3, 4, or 5. (Item 3) R Y4 Item 3. The compound according to item 2, wherein each instance of is independently hydrogen, —CH 3 , —CN, or —F. (Item 4) The compound according to item 2, wherein e is 3. (Item 5) R X is hydrogen. (Item 6) R Y4 Each instance of is independently hydrogen, —CH, —CN, or —F, and R X The compound according to item 2, wherein is hydrogen and e is 3. (Item 7) R Y4 Each instance of is independently hydrogen, —CH, —CN, or —F, and R X The compound according to item 2, wherein is hydrogen and e is 2. (Item 8) Item 3. The compound according to item 2, wherein e is 1. (Item 9) R Y4 The compound according to item 2, wherein is -F. (Item 10) R Y4 The compound according to item 2, wherein is -F and e is 1. (Item 11) The compound has the formula (1-A-2) [ka] Item 3. The compound according to item 2, wherein the compound is (Item 12) R Y4 Item 12. The compound according to item 11, wherein each instance of is independently hydrogen, —CH 3 , —CN, or —F. (Item 13) Item 12. The compound according to item 11, wherein e is 3. (Item 14) R X Item 12. The compound according to item 11, wherein is hydrogen. (Item 15) R Y4 Each instance of is independently hydrogen, —CH, —CN, or —F, and R X Item 12. The compound according to item 11, wherein is hydrogen and e is 3. (Item 16) R Y4 Each instance of is independently hydrogen, —CH, —CN, or —F, and R X Item 12. The compound according to item 11, wherein is hydrogen and e is 2. (Item 17) Item 12. The compound according to item 11, wherein e is 1. (Item 18) R Y4 Item 12. The compound according to item 11, wherein is -F. (Item 19) The compound has the formula (1-A-3) [ka] Item 11. The compound according to item 11, wherein in formula (1-A-3), R Y1 and R Y2 each is independently alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; Compounds where b=0, 1, 2, 3. (Item 20) The compound has the formula (1-A-4) [ka] Item 1. The compound according to item 1, (Item 21) R Y121. The compound according to item 20, wherein is hydrogen, —CH3, or —CH2CH3, —CH(CH3)2, or cycloalkyl. (Item 22) R 3 21. The compound according to item 20, wherein is Me, CF3, -CH2OMe, -CH2OEt. (Item 23) R Y2 21. The compound according to item 20, wherein is heterocyclyl, aryl, or heteroaryl. (Item 24) R Y2 is an aryl substituted with 0 to 5 -CH3, -CN, -F, -CF3, or a combination thereof, or a heteroaryl substituted with 0 to 5 -CH3, -CN, -F, -CF3. (Item 25) R X 21. The compound according to item 20, wherein is hydrogen, —CH3, or —CH2CH3. (Item 26) The compound has the formula (1-A-5) [ka] The compound according to item 1, which is a compound of In formula (1-A-5), R Y3 Each occurrence of is aryl or heteroaryl, and two R Y3 the groups are joined together to form a 6- to 10-membered ring; c is 0, 1, 2, or 3; The compound wherein d is 0, 1, 2, or 3. (Item 27) The compound has the formula (1-A-6) [ka] 27. The compound according to item 26, which is a compound of formula: (Item 28) The compound is represented by formula (1-A-7) or formula (1-A-8) [ka] 27. The compound according to item 26, which is a compound of formula: (Item 29) R 3 29. The compound according to item 28, wherein is —CH3, —CF3, —CH2OCH3, —CH2OCH2CH3. (Item 30) formula: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

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[0099] 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.

[0100] Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers 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., University 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.

[0101] 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 a nuclear Overhauser effect (NOE) experiment by nuclear magnetic resonance (NMR) spectroscopy.

[0102] In some embodiments, asymmetric centers of known absolute configuration can be introduced into compounds using chiral reactants, e.g., chiral amines. In some embodiments, asymmetric centers of known absolute configuration can be introduced into compounds using reaction methods, e.g., by reductive amination.

[0103] 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.

[0104] 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.

[0105] 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.

[0106] 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:

[0107] 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.

[0108] "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 1~5In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1~4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1~3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1~2 In some embodiments, an alkyl group has one carbon atom ("C alkyl"). 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)).

[0109] "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 2~20 In 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), butadienyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each occurrence of an alkenyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C2~10 In certain embodiments, the alkenyl group is a substituted C 2~10 It is alkenyl.

[0110] "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 In some embodiments, an 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 2~4Alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Further examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each occurrence of an alkynyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents; for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2~10 In certain embodiments, the alkynyl group is a substituted C 2~10 It is alkynyl.

[0111] "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, the aryl group has 14 ring carbon atoms ("C 14"Aryl"; e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, where the bonding radical or 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 substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6~14 In certain embodiments, the aryl group is a substituted C 6~14 It is aryl.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] "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.

[0117] "Hydroxy" or "hydroxyl," unless otherwise stated, by themselves or as part of another substituent, mean an --OH group.

[0118] "Hydroxyalkyl" or "hydroxylalkyl" can include alkyl structures substituted with one or more hydroxyl groups.

[0119] "Heteroaryl" refers to a radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or □□□□ 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 with 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. For bicyclic heteroaryl groups that do not contain heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on the ring with the heteroatom (e.g., 2-indolyl) or the ring without the heteroatom (e.g., 5-indolyl).

[0120] 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.

[0121] 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.

[0122] 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.

[0123] "Carbocyclyl" or "carbocyclic" means a ring system having 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10 carbocyclyl). Exemplary C 3~6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. 3~8 The carbocyclyl group includes the above-mentioned C 3~6 Examples include, but are not limited to, carbocyclyl groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. 3~10 The carbocyclyl group includes the above-mentioned C 3~8 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, the carbocyclyl group is a substituted C 3~10 It is a carbocyclyl.

[0124] 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.

[0125] "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.

[0126] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heterocyclyl"). In some embodiments, a 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl is selected from nitrogen, oxygen, and In some embodiments, the 5- or 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0127] 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.

[0128] 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 include acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (e.g., amido), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, keto, nitro, thiol, - It may be optionally substituted with one or more groups selected from -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.

[0129] "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).

[0130] "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 At least one of is other than H.

[0131] "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.

[0132] "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.

[0133] 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.

[0134] "Amino" refers to the -NH2 radical.

[0135] "Oxo" refers to the group =O.

[0136] "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 is not hydrogen. And each R 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.

[0137] 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.

[0138] "Azide" refers to the -N3 radical.

[0139] "Carbamoyl" or "amide" refers to the -C(O)NH2 radical.

[0140] "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.

[0141] "Carboxy" refers to the radical --C(O)OH.

[0142] "Cyano" refers to the -CN radical.

[0143] "Nitro" refers to the -NO2 radical.

[0144] "Ethenyl" refers to substituted or unsubstituted -(C=C)-. "Ethylene" refers to substituted or unsubstituted -(CC)-. "Ethynyl" refers to -(C≡C)-.

[0145] 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.

[0146] 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.

[0147] 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 、-SC(=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, independently, 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 ee )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, independently, 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; R ffEach 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 1~6 alkyl), -N(C1~6 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 2~6 Alkynyl, C3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl; - is the counter ion.

[0148] 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.).

[0149] 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, -SO2Rcc , -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.

[0150] 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(R cc)2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , C 1~10 Alkyl, C 2~10 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).

[0151] 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)).

[0152] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (hydroxyl The oxygen protecting group is -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).

[0153] 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).

[0154] 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).

[0155] 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.

[0156] 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.

[0157] "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).

[0158] "Pharmaceutically acceptable salts" refers to salts of the compounds of the present invention that are pharmaceutically acceptable and 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 of inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc. , nitric acid, phosphoric acid, etc.; or 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, camphorsulfonic acid, 4-methylbicyclo[2.2. or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, alkaline earth ion, or aluminum ion, or coordinates with an organic base, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like. Salts also include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and, if the compound contains a basic functional group, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion of an acidic functional group. Such cations are exemplified by sodium cations, potassium cations, calcium cations, magnesium cations, ammonium cations, tetraalkylammonium cations, etc. See, e.g., Berge et al., J. Pharm. Sci. (1977) 66(1):1-79.

[0159] "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.

[0160] "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."

[0161] "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 movement of π electrons and atoms (usually H). For example, enols and ketones are rapidly interconverted by treatment with either acid or base, and are therefore tautomers. 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.

[0162] "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.

[0163] Disease, disorder, and condition are used interchangeably herein.

[0164] 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").

[0165] 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.

[0166] 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.

[0167] 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.

[0168] Detailed Description of Specific Embodiments of the Invention Provided herein are compounds (eg, compounds of Formula (I)), pharmaceutical compositions, and methods of use thereof for treating the diseases or disorders described herein.

[0169] 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.

[0170] In one aspect, the compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein in formula (I), R 2 , R 4 , R 6 , R 7 , 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 ,-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 with the carbon atom to which they are attached form a carbocyclyl, heterocyclyl, or -C(=O)-; R 3 is hydrogen, alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; R 17a and R 17b 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 , -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 where R 17a and R 17b At least one of R is not hydrogen; 19 is hydrogen or alkyl (e.g., unsubstituted alkyl or substituted alkyl (e.g., —C(R C )2OR A1 where R C is hydrogen or alkyl; R 5 is absent or is hydrogen; [ka] represents a single or double bond, where one [ka] is a double bond, the other [ka] is a single bond, and R 5 does not exist.

[0171] In some embodiments, R 19 is hydrogen or alkyl. In some embodiments, R 19 is unsubstituted alkyl. In some embodiments, R 19 is substituted alkyl. In some embodiments, R 19 is -CH2OH, -CH2OCH3, -CH2OCH2CH3, or -CH2OCH(CH3)2.

[0172] In some embodiments, R 2 is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , or -N(R A1 )2. In some embodiments, R 2 is hydrogen, halogen, alkyl, or -OR A1 In some embodiments, R 2 is hydrogen.

[0173] In some embodiments, R 3 is alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, R 3 is alkyl (e.g., substituted or unsubstituted alkyl), alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, R 3 is methyl and ethyl (e.g., substituted or unsubstituted alkyl).

[0174] In some embodiments, R 4 is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , or -N(R A1 )2. In some embodiments, R 4 is hydrogen, halogen, alkyl, or -OR A1In some embodiments, R 4 is hydrogen.

[0175] In some embodiments, [ka] represents a single bond, and R 5 is hydrogen. In some embodiments, R 5 does not exist, [ka] represents a single or double bond, where one [ka] is a double bond, the other [ka] is a single bond.

[0176] In some embodiments, R 6 is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , or -N(R A1 )2. In some embodiments, R 6 is hydrogen, halogen, alkyl, or -OR A1 In some embodiments, R 6 is hydrogen.

[0177] In some embodiments, R 7 is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , or -N(R A1 )2. In some embodiments, R 7 is hydrogen, halogen, alkyl, or -OR A1 In some embodiments, R7 is hydrogen.

[0178] In some embodiments, R 11a is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2 or R 11a and R 11b together with the carbon atom to which they are attached form -C(=O)-. In some embodiments, R 11a is hydrogen, halogen -N, alkyl, or -OR A1 In some embodiments, R 11a and R 11b together with the carbon atom to which they are attached form -C(=O)-. In some embodiments, R 11a and R 11b is hydrogen.

[0179] In some embodiments, R 2 , R 4 , R 6 , R 7 , R 11a , and R 11b each independently represents hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , or -N(R A1 )2. In some embodiments, R 2 , R 4 , R 6 , R 7 , R 11a , and R 11b each independently represents hydrogen, halogen, alkyl, or -OR A1 In some embodiments, R 2 , R 4 , R 6 , R 7 , R 11a , and R 11b is hydrogen.

[0180] In some embodiments, R 17a and R 17b each independently represents hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, -SR A1 , -N(R A1 )2, -NHC(=O)R A1 -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 where R 17a and R 17b In some embodiments, at least one of R 17a and R 17b each independently represents hydrogen, halogen, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, -SR A1 , -N(R A1 )2, -NHC(=O)R A1 -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 where R 17a and R 17b At least one of the is not hydrogen.

[0181] In some embodiments, R 17a is halogen, cyano, nitro, alkyl, carbocyclyl, heterocyclyl, -OR A1 , -SR A1 , -N(R A1 )2, -NHC(=O)R A1 , -S(=O)R A2 , or -SO2R A2 In some embodiments, R 17a is halogen, nitro, alkyl, carbocyclyl, heterocyclyl, -OR A1 , -SR A1 , -N(R A1 )2, -NHC(=O)R A1 , -S(=O)R A2 , or -SO2R A2In some embodiments, R 17a is halogen, cyano, nitro, alkyl, -OR A1 , -SR A1 , or -N(R A1 )2.

[0182] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0183] In one aspect, the compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein in formula (II), R 2 , R 4 , R 6 , R 7 , 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 with the carbon atom to which they are attached form a carbocyclyl, heterocyclyl, or -C(=O)- group; R 3 is hydrogen, alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; A is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, -OR A1 , -SR A1 , or -N(R A1 )2;R 19 is hydrogen or alkyl (e.g., unsubstituted alkyl (e.g., —CH) or substituted alkyl (e.g., —C(R C )2OR A1 where R C is hydrogen or alkyl; R 5 is absent or is hydrogen; [ka] represents a single or double bond, where one [ka] is a double bond, the other [ka] is a single bond, and R 5 does not exist.

[0184] In some embodiments, A is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, or -OR A1 is.

[0185] In some embodiments, R 19 is hydrogen. In some embodiments, R 19is alkyl (e.g., substituted or unsubstituted alkyl). In some embodiments, R 19 is -CH3 or -CH2CH3. In some embodiments, R 19 is -C(R C )2OR A1 In some embodiments, R 19 is -CH2OH, -CH2OCH3, -CH2OCH2CH3, or -CH2OCH(CH3)2.

[0186] In some embodiments, R 2 is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , or -N(R A1 )2. In some embodiments, R 2 is hydrogen, halogen, alkyl, or -OR A1 In some embodiments, R 2 is hydrogen.

[0187] In some embodiments, R 3 is alkyl (e.g., substituted or unsubstituted alkyl). In some embodiments, R 3 is methyl and ethyl (eg, substituted or unsubstituted methyl, substituted or unsubstituted ethyl).

[0188] In some embodiments, R 4 is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , or -N(R A1 )2. In some embodiments, R 4 is hydrogen, halogen, alkyl, or -OR A1 In some embodiments, R 4 is hydrogen.

[0189] In some embodiments, [ka] represents a single bond, and R 5 is hydrogen. In some embodiments, R 5 does not exist, [ka] represents a single or double bond, where one [ka] is a double bond, the other [ka] is a single bond.

[0190] In some embodiments, R 6 is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , or -N(R A1 )2. In some embodiments, R 6 is hydrogen, halogen, alkyl, or -OR A1 In some embodiments, R 6 is hydrogen.

[0191] In some embodiments, R 7 is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , or -N(R A1 )2. In some embodiments, R 7 is hydrogen, halogen, alkyl, or -OR A1 In some embodiments, R 7 is hydrogen.

[0192] In some embodiments, R 11ais hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2 or R 11a and R 11b together with the carbon atom to which they are attached form -C(=O)-. In some embodiments, R 11a is hydrogen, halogen, alkyl, or -OR A1 In some embodiments, R 11a and R 11b together with the carbon atom to which they are attached form -C(=O)-. In some embodiments, R 11a and R 11b is hydrogen.

[0193] In some embodiments, R 2 , R 4 , R 6 , R 7 , R 11a , and R 11b each independently represents hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , or -N(R A1 )2. How many In some embodiments, R 2 , R 4 , R 6 , R 7 , R 11a , and R 11b Each of is hydrogen, halogen, alkyl, or -OR A1 In some embodiments, R 2 , R 4 , R 6 , R 7 , R 11a , and R 11b Each of is hydrogen.

[0194] In some embodiments, the compound of Formula (II) has the formula (II-a) or (II-b): [ka] is a compound of

[0195] In some embodiments, the compound of Formula (I) has the formula (II-c): [ka] In the formula (II-c), R 21a and R 21b 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 or R 21a and R 21b together with the carbon atom to which they are attached form a carbocyclyl, heterocyclyl, or -C(=O)- group; Q is hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR A1 , -SR A1 , or -N(R A1 ) 2; and n is an integer selected from 1, 2, and 3.

[0196] In some embodiments, the compound of Formula (II) has the formula (II-d): [ka] is a compound of

[0197] In one aspect, the compound of formula (III-a): [ka] or a pharmaceutically acceptable salt thereof, wherein in formula (III-a), R 2 , R 4 , R 6 , R 7 , 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 with the carbon atom to which they are attached form a carbocyclyl, heterocyclyl, or -C(=O)- group; Q is hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, -OR A1 , -SR A1 , or -N(R A1 )2;R 19 is unsubstituted alkyl; R 5 is absent or is hydrogen; [ka] represents a single or double bond, where one [ka] is a double bond, the other [ka] is a single bond, and R 5 does not exist.

[0198] In one aspect, the compound of formula (III-b): [ka] or a pharmaceutically acceptable salt thereof, wherein in formula (III-b), R 2 , R 4 , R 6 , R 7 , 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 11btogether with the carbon atom to which they are attached form a carbocyclyl, heterocyclyl, or -C(=O)- group; R 3 is alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; Q is halogen, cyano, nitro, heterocyclyl linked via a C atom, aryl, heteroaryl linked via a C atom, -O-alkenyl, -O-alkynyl, -SR A1 , -N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 , -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 and;R 19 is -C(R C )2OR A1 where R C is hydrogen or alkyl; R 5 is absent or is hydrogen; [ka] represents a single or double bond, where one [ka] is a double bond, the other [ka] is a single bond, and R 5 does not exist.

[0199] In one aspect, the compound of formula (1-A): [ka] or a pharmaceutically acceptable salt thereof, wherein in formula (1-A), R 3 is alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; R X and R Yeach is independently hydrogen, aryl, or alkyl; R X and R Y are bonded together to form a 3- to 10-membered heterocyclic ring; R 19 is hydrogen or alkyl (e.g., unsubstituted alkyl or substituted alkyl (e.g., —C(R C )2OR A1 where R C is hydrogen or alkyl; R 5 is absent or is hydrogen; [ka] represents a single or double bond, where one [ka] is a double bond, the other [ka] is a single bond, and R 5 is absent; a is 0 or 1; provided that if and only if a is 0, then R X and R Y are bonded together to form a 3- to 8-membered heterocycle.

[0200] In some embodiments, R X and R Y In some embodiments, R 3 is alkyl. In some embodiments, R 19 is hydrogen.

[0201] In some embodiments, the compound has the formula (1-A-1): [ka] In formula (1-A-1), R Y4Each instance of is independently alkyl, cyano, or halo; and e is 0, 1, 2, 3, 4, or 5.

[0202] In some embodiments, R Y4 Each instance of is independently hydrogen, —CH, —CN, or —F. In some embodiments, e is 3. In some embodiments, R X is hydrogen. In some embodiments, R Y4 Each instance of is independently hydrogen, —CH, —CN, or —F, and R X is hydrogen and e is 3. In some embodiments, R Y4 Each instance of is independently hydrogen, —CH, —CN, or —F, and R X is hydrogen and e is 2. In some embodiments, e is 1. In some embodiments, R Y4 is -F. In some embodiments, R Y4 is -F and e is 1.

[0203] In some embodiments, the compound has the formula (1-A-2): [ka] is a compound of

[0204] In some embodiments, R Y4 Each instance of is independently hydrogen, —CH, —CN, or —F. In some embodiments, e is 3. In some embodiments, R X is hydrogen. In some embodiments, R Y4 Each instance of is independently hydrogen, —CH, —CN, or —F, and R X is hydrogen and e is 3. In some embodiments, R Y4 Each instance of is independently hydrogen, —CH, —CN, or —F, and R Xis hydrogen and e is 2. In some embodiments, e is 1. In some embodiments, R Y4 is -F.

[0205] In some embodiments, the compound has the formula (1-A-3): [ka] In formula (1-A-3), R Y1 and R Y2 each is independently alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and b=0, 1, 2, 3.

[0206] In some embodiments, R Y1 and R Y2 Not both are -CH(CH3)2. In some embodiments, the compound has the formula (1-A-4): [ka] is a compound of

[0207] In some embodiments, R Y1 is hydrogen, —CH, or —CHCH, —CH(CH), or cycloalkyl. 3 is —CH, —CF, —CHOCH, —CHOCHCH. In some embodiments, R Y2 is heterocyclyl, aryl, or heteroaryl. In some embodiments, R Y2 is aryl substituted with 0-5 -CH3, -CN, -F, -CF3, or a combination thereof, or heteroaryl substituted with 0-5 -CH3, -CN, -F, -CF3.

[0208] In some embodiments, R Y2is aryl substituted with 0 to 5 -CH3, -CN, -F, or -CF3, or R X is hydrogen, —CH, or —CHCH. In some embodiments, R Y2 is aryl substituted with 0 to 5 -CH3, -CN, -F, or -CF3.

[0209] In some embodiments, the compound has the formula (1-A-5): [ka] In formula (1-A-5), R Y3 Each occurrence of is aryl or heteroaryl, or two R Y3 the groups are joined together to form a 6- to 10-membered ring; c is 0, 1, 2, or 3; d is 0, 1, 2, or 3.

[0210] In some embodiments, the compound has the formula (1-A-6): [ka] is a compound of

[0211] In some embodiments, when d is 2, two R Y3 The groups are joined together to form an aryl. In some embodiments, R Y2 is aryl substituted with 0-5 -CH, -CN, -F, -CF. In some embodiments, the compound has formula (1-A-7) or formula (1-A-8): [ka] is a compound of

[0212] In some embodiments, R Y2 is aryl substituted with 0 to 5 -CH3, -CN, -F, or -CF3, or R 3are -CH3, -CF3, -CH2OCH3, -CH2OCH2CH3.

[0213] In one aspect, the formula (2-A) [ka] or a pharmaceutically acceptable salt thereof, wherein in formula (2-A), R 3 is -CH3, -CF3, -CH2OCH3, -CH2OCH2CH3; R 19 is hydrogen, -CH3, or -CH2OR A1 where R A1 is optionally substituted alkyl; R 3 is -CH3, -CF3, -CH2OCH3, -CH2OCH2CH3; R 17a is -NR A2 R A3 , -N(R1)C(O)R A2 , -N(R1)SO2R A2 , -OR A3 , cycloalkyl, heterocyclyl, aryl, or heteroaryl, where R A2 and R A3 each independently represents hydrogen, carbocyclyl, heterocyclyl, aryl, heteroaryl, or -OR A4 where R A4 is hydrogen or alkyl; or R 17A teeth, [ka] where A is oxazolyl or thiazolyl; R 17b is hydrogen, hydroxyl, alkyl, or alkoxy; [ka] represents a single or double bond, where one [ka] is a double bond, the other [ka] is a single bond, and R 5 does not exist; however, R 17a is oxazolyl or [ka] If R 17b is not hydrogen or R 17a When is heterocyclyl, R 19 is hydrogen, or R 17a -OR A4 If R 19 is hydrogen, This is subject to the following conditions.

[0214] In some embodiments, R 17a is -NR A2 R A3 , -N(R1)C(O)R A2 , -N(R1)SO2R A2 In some embodiments, R 17a is aryl, heteroaryl, cycloalkyl, or heterocyclyl. In some embodiments, R 19 is hydrogen. In some embodiments, R 17a is heteroaryl. In some embodiments, R 17a is heteroaryl and R 19 is hydrogen. In some embodiments, R 17a is pyridyl and R 19 is hydrogen.

[0215] In one aspect, the formula (3-A) [ka] or a pharmaceutically acceptable salt thereof, wherein in formula (3-A), R 19 is hydrogen or alkyl; R 17ais nitro or alkoxy (e.g., -OCH3); R 2 , R 4 , R 11a , or R 11b each is independently hydrogen, alkyl, or alkoxy, or R 11a and R 11b together to form oxo; [ka] represents a single or double bond, where one [ka] is a double bond, the other [ka] is a single bond, and R 5 does not exist;R 5 is absent or hydrogen as determined by valence; provided that R 2 , R 11a , and R 11b is hydrogen, R 4 is alkyl, or R 4 , R 11a , and R 11b is hydrogen, R 2 is alkyl, or R 4 is hydrogen, R 2 is —OH or alkoxy, and R 11a is hydrogen and R 11b is —OH or alkoxy, or R 2 is —OH or alkoxy, and R 11a and R 11b are taken together to form oxo.

[0216] In some embodiments, R 4 is hydrogen and R 2 is —OH or alkoxy, and R 11a is hydrogen and R 11bis —OH or alkoxy. In some embodiments, R 4 is hydrogen and R 2 is —OH or alkoxy, and R 11a and R 11b taken together form oxo. In some embodiments, R 17a is nitro. In some embodiments, R 17a is alkoxy. In some embodiments, R 17a is methoxy and R 2 is methyl.

[0217] Further provided herein are the compounds set forth in Table 1 below, or pharmaceutically acceptable salts thereof.

[0218] [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] [Table 1-20] [Table 1-21] [Table 1-22]

[0219] Alternative Embodiments In an alternative embodiment, the compounds described herein also comprise: 1 It may contain one or more isotopic substitutions other than the replacement of H with deuterium. For example, hydrogen may also be 3 H (T or tritium); carbon can be, for example, 13 C or 14 C; oxygen can be, for example, 18 O; nitrogen can be, for example, 15 N, etc. In other embodiments, a specific isotope (e.g., 3H, 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.

[0220] 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.

[0221] The pharmaceutical compositions provided herein can be administered by a variety of routes, including oral (enteral), parenteral (by injection), rectal, transdermal, intradermal, intrathecal, subcutaneous (SC), intravenous, The compounds may be administered by intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration, but are not limited to these.

[0222] 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 route of administration, the actual compound being administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.).

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

[0224] 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.

[0225] 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.

[0226] 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.

[0227] 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.

[0228] 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.

[0229] 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.

[0230] 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).

[0231] 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.

[0232] 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.

[0233] 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.

[0234] 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.

[0235] 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.

[0236] The present invention also relates to pharmaceutically acceptable acid addition salts of the compounds of the present invention. The acids that can be used to prepare pharmaceutically acceptable salts are non-toxic acid addition salts, i.e., pharmacologically acceptable. Acids that form salts with acceptable anions (e.g., hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, etc.).

[0237] 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.

[0238] 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).

[0239] 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.

[0240] 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 α-1,4-linked glucose units, respectively, optionally containing one or more substituents on the attached 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).

[0241] 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 prior to use.

[0242] 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.).

[0243] 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 material 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 consisting of various vehicles or carriers and other components useful for forming the desired dosage form. It is a processing aid.

[0244] 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.

[0245] 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.

[0246] Methods of Use and Treatment In yet another aspect, a method of reducing or preventing seizure activity in a subject is provided, 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.

[0247] 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 modulation include sleep disorders [e.g., insomnia], mood disorders [e.g., depression, dysthymic disorder (e.g., mild depression), bipolar disorder (e.g., Type I and / or Type II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD))], schizophrenia spectrum disorders [e.g., schizophrenia, schizoaffective disorder], seizure disorders [e.g., epilepsy (e.g., status epilepticus (SE)), seizures], memory and / or cognition disorders [e.g., attention disorders (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.

[0248] In yet another aspect, there is provided a combination of a compound of the present invention with another pharmacologically active agent. The compounds provided herein can be administered as the sole active agent or Administration in combination may proceed by any technique apparent to one skilled in the art, including, for example, separate, sequential, simultaneous, and alternating administration.

[0249] 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.

[0250] 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.

[0251] 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.

[0252] 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.

[0253] 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.

[0254] 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.

[0255] 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.

[0256] In yet another aspect, there is provided a method of treating an attention disorder by administering to a subject a therapeutically effective amount of a compound of the invention. In certain embodiments, the attention disorder is ADHD.

[0257] 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.

[0258] 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 that 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, a neuroendocrine disorder or dysfunction is associated with a women's health disorder or condition (e.g., a women's health disorder or condition described herein). In some embodiments, a women's health disorder or condition is associated with a women's health disorder or condition. A related neuroendocrine disorder or dysfunction is polycystic ovary syndrome.

[0259] 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.

[0260] Neurodegenerative Diseases and DisordersThe present invention provides a method 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 mild, moderate, or severe cognitive impairment associated symptoms); amyotrophic lateral sclerosis (ALS); anoxic and ischemic damage; ataxia and seizures (including for treatment and prevention, and for the prevention of seizures caused by schizoaffective disorder or drugs used to treat schizophrenia); benign amnesia; cerebral edema; cerebellar ataxia (including McLeod neuroacanthocytosis syndrome (MLS)); closed head injury; coma; contusion injury (for example, 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 tremor tremors (e.g., psycholeptic-induced acute akathisia, acute ataxia, tremor tremors 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) syndromes (including brainstem neurocalcification, corticobasal degeneration, multiple system atrophy, tremor tremors-ALS dementia complex, Parkinson's disease, postencephalitic tremor tremors, and progressive supranuclear palsy);Muscle spasms 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), dyskinesias (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 ataxias (axial ataxia, dystonic writer's cramp, hemiplegic ataxia, paroxysmal ataxia, and focal ataxias (e.g., blepharospasm, oromandibular dystonia) Neurodegenerative diseases include, but are not limited to, neuronal damage (including eye damage, ocular retinopathy or macular degeneration); stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and neurotoxicity after cardiac arrest; Parkinson's disease; seizures; status epilepticus; stroke; tinnitus; renal tubular sclerosis, and neurodegeneration induced by viral infection (such as those caused by acquired immunodeficiency 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 after cardiac arrest. Methods of treating or preventing neurodegenerative diseases also include treating or preventing the loss of neuronal function that is characteristic of neurodegenerative disorders.

[0261] Mood disorders Mood disorders, such as clinical depression, postpartum or postnatal depression, perinatal depression, atypical depression, melancholic depression, psychogenic major depression, catatonic depression, seasonal affective disorder, mood Also provided herein are methods for treating mood disorders, 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).

[0262] 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.

[0263] 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.

[0264] 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).

[0265] In some embodiments, the subject with PND also experiences depression or symptoms of depression during pregnancy.This depression is referred to herein as perinatal depression.In some embodiments, the subject who experiences perinatal depression has a high risk of experiencing PND.

[0266] 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.

[0267] 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.

[0268] 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.

[0269] Catatonic depression refers to major depression accompanied by impaired motor behavior and other symptoms. The individual may become mute and stuporous and may become immobile. or exhibit purposeless or bizarre movements.

[0270] 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.

[0271] 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).

[0272] Dual depression refers to a severely depressed mood (dysthymia) lasting at least two years and interrupted by periods of major depression.

[0273] Depressive personality disorder (DPD) refers to a personality disorder with depressive features.

[0274] Recurrent Brief Depression (RBD) refers to a condition in which an individual has depressive episodes approximately once per month, each lasting two weeks or less, typically less than two to three days.

[0275] Minor depressive disorder or minor depression refers to depression in which at least two symptoms are present for two weeks.

[0276] 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.

[0277] Chronic condition-induced depression refers to depression caused by a chronic medical condition such as cancer or chronic pain, chemotherapy, or chronic stress.

[0278] 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).

[0279] 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.

[0280] 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).

[0281] 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.

[0282] 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).

[0283] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a decrease in the Hamilton Rating Scale for Depression (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.

[0284] 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; 7-19 indicates mild depression; 20-34 indicates moderate depression; and >34 indicates severe depression. In some embodiments, the therapeutic effect is a reduction from baseline in the MADRS score at the end of the treatment period (e.g., 12 hours, 24 hours, 48 ​​hours; 24 hours, 48 ​​hours, 60 hours, 72 hours, 96 hours, or more after administration). In some embodiments, the reduction from baseline in the MADRS score 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.

[0285] 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.

[0286] 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.

[0287] 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. Anxiety disorders

[0288] 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.

[0289] 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.

[0290] In panic disorder, a person suffers from brief attacks of intense fear and anxiety, often characterized by trembling, shaking, confusion, dizziness, nausea, and difficulty breathing. Panic attacks (defined by the APA as fear or discomfort that occurs unexpectedly and 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, 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 heartbeat are noticed by the panic sufferer, leading them to believe that something is wrong with their heart or that they are having another panic attack. In some cases, a heightened perception of bodily functions (hypervigilance) occurs during a panic attack, in which any perceived physiological changes are interpreted as a possible life-threatening illness (i.e., excessive hypochondria).

[0291] 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.

[0292] 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).

[0293] 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.

[0294] 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).

[0295] 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.

[0296] 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.

[0297] 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).

[0298] 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.

[0299] Miscarriage refers to the spontaneous termination of a pregnancy within 20 weeks of gestation.

[0300] Abortion refers to the intentional termination of a pregnancy, which can occur up to 28 weeks into pregnancy.

[0301] Infertility and related disorders include uterine fibroids, polycystic ovary syndrome, endometriosis, and primary ovarian insufficiency.

[0302] 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.

[0303] Other disorders and conditions that affect only women include Turner syndrome, Rett syndrome, and ovarian and cervical cancer.

[0304] 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.

[0305] Menopause refers to 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, such as hot flashes and emotional symptoms of menopause, can disrupt sleep, reduce energy, or cause anxiety, sadness, or a sense of loss.Menopause includes natural menopause and surgical menopause (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 drug therapy.

[0306] epilepsy The compounds described herein, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable compositions thereof, can be used in the methods described herein, e.g., for the treatment of a disorder described herein, e.g., epilepsy, status epilepticus, or seizures, as described in WO2013 / 112605 and WO / 2014 / 031792, the contents of which are incorporated herein in their entireties.

[0307] Epilepsy is a brain disorder characterized by repeated seizures over a long period of time. Types of epilepsy include, but are not limited to, generalized epilepsy, e.g., childhood absence epilepsy. These may include epilepsy, juvenile myoclonic epilepsy, epilepsy with awakening grand mal seizures, West syndrome, Lennox-Gastaut syndrome, partial epilepsies such as temporal lobe epilepsy, frontal lobe epilepsy, benign focal epilepsy of childhood.

[0308] 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).

[0309] 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.

[0310] 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.

[0311] The compositions described herein can also be administered as prophylaxis to subjects with a CNS disorder, e.g., traumatic brain injury, status epilepticus, e.g., convulsive 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, prior to the onset of a seizure.

[0312] 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.

[0313] 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.

[0314] 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.

[0315] 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.

[0316] 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."

[0317] 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.

[0318] Clonic seizures are recurrent rhythmic spasms that involve both sides of the body simultaneously.

[0319] Tonic seizures are characterized by muscle stiffness.

[0320] Atonic seizures consist of a sudden loss of muscle tone throughout the body, especially the arms and legs, often resulting in a fall.

[0321] Seizures described herein can include epileptic seizures; acute repetitive seizures; cluster seizures; continuous seizures; continuous seizures; persistent seizures; recurrent seizures; status epilepticus, e.g., refractory convulsive status epilepticus, non-convulsive status epilepticus; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondarily generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign rolandic seizures; febrile seizures; affective seizures; focal seizures; galactocele; generalized onset seizures; infantile spasms; Jackson seizures; generalized bilateral myoclonic seizures; multifocal seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post-traumatic seizures; petit mal seizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures. In some embodiments, the seizures are generalized seizures associated with Dravet syndrome, Lennox-Gastaut syndrome, tuberous sclerosis complex, Rett syndrome, or PCDH19 female epilepsy.

[0322] 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.

[0323] shaking The methods described herein can be used to treat tremor, 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, tricyclic antidepressants, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, and vincristine); and psychogenic disorders. Clinical tremor includes physiological tremor, fatigue-induced physiological tremor, and enhanced physiologic tremor. tremor), essential tremor syndromes (including classic essential tremor, primary orthostatic tremor, and task-specific and position-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.

[0324] 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).

[0325] 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).

[0326] 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.

[0327] Essential tremor, or benign essential tremor, is the most common type of tremor. Essential tremor can be mild and non-progressive in some cases, or it can be slowly progressive, starting on one side of the body but affecting both sides within three years. The hands are most frequently affected, but the head, voice, tongue, legs, and trunk can also be involved. Tremor frequency can decrease with age, but severity can increase. Emotional excitement, stress, fever, physical fatigue, or hypoglycemia can trigger tremor and / or increase its severity. Symptoms generally develop over a long period of time and can become visible and persist after onset.

[0328] 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.

[0329] 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.

[0330] 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.

[0331] 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.

[0332] 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.

[0333] 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.

[0334] 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.

[0335] Chorea is a neurological disorder characterized by rhythmic involuntary movements that typically affect the shoulders, buttocks, and face.

[0336] 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.

[0337] Ataxia refers to the loss of complete control of bodily movements and can affect fingers, hands, arms, legs, body, speech and eye movements.

[0338] Myoclonus and startle are reactions to sudden and unexpected stimuli that can be auditory, tactile, visual, or vestibular.

[0339] 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.

[0340] Restless legs syndrome is a neurological sensorimotor disorder characterized by an irresistible urge to move the legs while at rest.

[0341] Stiff-person syndrome is a progressive movement disorder characterized by involuntary painful spasms and muscle stiffness, usually involving the hips and legs. It typically results in a stiff gait with excessive lumbar hyperlordosis. It is typically accompanied by continuous motor monotony of the paraspinal axial muscles. Characteristic abnormalities in EMG recordings of positional activity are seen. Variants include "stiff-limb syndrome," which results in focal stiffness, typically affecting the distal legs and feet.

[0342] 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.

[0343] 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.

[0344] Sedation is the reduction of irritability or agitation, typically through the administration of a pharmacological agent, to facilitate a medical or diagnostic procedure. Sedation and analgesia encompass a continuum of states of consciousness ranging from minimal sedation (anxiolysis) to general anesthesia.

[0345] 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.

[0346] 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.

[0347] 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.

[0348] 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.

[0349] Sedation in the intensive care unit (ICU) allows for a patient 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 the patient's illness. Heavy sedation in intensive care is used to facilitate endotracheal tube tolerance and ventilator synchronization (often accompanied by neuromuscular blocking agents). It is used in.

[0350] 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.

[0351] 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]

[0352] 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. material and method

[0353] 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.

[0354] 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.

[0355] 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.

[0356] 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.

[0357] Exemplary general method for analytical HPLC: Mobile phase: A: water (10 mM NH4HCO3), B: acetonitrile; Gradient: 5% to 95% B in 1.6 or 2 min; Flow rate: 1.8 or 2 mL / min; Column: XBridge C18, 4.6 x 50 mm, 3.5 μm, 45 °C

[0358] 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. Exemplary LCMS conditions include: [Table A] [Table B] [Table C]

[0359] 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).

[0360] 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 5 mL aliquots 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 lower by F-test, the data were fitted to a partial inhibition model instead of a complete inhibition model. Similarly, if the sum of squares is significantly lower by the F-test, the data are fitted to a two-component inhibition model instead of a one-component inhibition model. The concentration of test compound that produces 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.

[0361] 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.

[0362] 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: ethylmagnesium 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.

[0363] Example 1. Synthesis of Compound 1 [ka] The synthesis of A1 is disclosed in WO2013 / 56181A1.

[0364] Step 1 (A2). Liquid bromine (7.46 g, 46.7 mmol) was slowly added to vigorously stirred aqueous sodium hydroxide solution (62.3 mL, 3 M, 187 mmol) at 0 °C. Once all the bromine had dissolved, the mixture was diluted with cold dioxane (15 mL) and slowly added to a stirred solution of A1 (5 g, 15.6 mmol) in dioxane (20 mL) and water (15 mL). The homogeneous yellow solution slowly turned colorless, and a white precipitate formed. The reaction mixture was stirred at 25 °C for 16 h. The remaining oxidant was quenched with aqueous NaSO (30 mL), and the mixture was then heated at 80 °C until the solid material dissolved. The solution was acidified with hydrochloric acid (3 N), resulting in the formation of a white precipitate. The solid was collected by filtration and washed with water (3 × 100 mL) to give a solid that was dried in vacuo to give the crude product. The crude product was triturated with toluene (40 mL) to give A2 (3.6 g, 72%) as a solid. 1 H NMR (CDCl3,400MHz) δ 2.43-2.38 (m, 1H), 2.07-2.04 (m, 2H), 1.82-1.79 (m, 4H), 1.57-1.60 (m, 3H), 1.57-1.40 (m, 7H), 1.39-1.30 (m, 8H), 1.29-1.06 (m, 3H), 0.72 (s, 3H).

[0365] Step 2 (Compound 1) To a solution of A2 (100 mg, 0.312 mmol) in DCM (8 mL) was added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25° C. After stirring for 30 min at 25° C., phenylmethylamine (53.4 mg, 0.499 mmol) was added. The mixture was stirred at 25° C. for 12 h. Water (8 mL) was added. The mixture was extracted with DCM (2×8 mL). The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo to give the crude product, which was purified by preparative HPLC (column: Xtimate C18 150 × 25 mm × 5 um; conditions: water (0.05% ammonia hydroxide v / v)-ACN; gradient 50% to 80% B; gradient time (min): 10) and lyophilized to give compound 1 (77 mg, 61%) as a solid. 1 H NMR (CDCl3,400MHz) δ 7.40-7.26 (m, 5H), 5.54 (s, 1H), 4.55-4.35 (m, 2H), 2.25-2.10 (m, 2H), 1.96-1.60 (m, 8H), 1.57-1.30 (m, 6H), 1.25-1.15 (m, 8H), 1.15-1.00 (m, 4H), 0.71 (s, 3H). LCMS Rt=1.797 min (3 min chromatography), 30-90CD, purity 100%, C 27 H 40 NO2 + [M+H] + MS ESI calculated value 410, measured value 410.

[0366] Example 2. Synthesis of Compound 2 [ka]

[0367] Step 1 (Compound 2). To a solution of A2 (100 mg, 0.312 mmol) in DCM (8 mL) was added TEA (236 mg, 2.34 mmol) and HATU (266 mg, 0.702 mmol). After stirring for 10 min, diethylamine (54.7 mg, 0.749 mmol) was added. The mixture was stirred at 25 °C for 12 h. The reaction was treated with water (8 mL) and extracted with DCM (2 × 8 mL). The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo to give the crude product, which was purified by preparative HPLC (Column: Xtimate C18 150 × 25 mm × 5 μm; Conditions: water (0.05% ammonia hydroxide v / v)-ACN; Gradient 52% to 82% B; Gradient time (min): 10) and lyophilized to give Compound 2 (100 mg, 57%) as a solid. 1 H NMR (CDCl3,400MHz) δ 3.77-3.65 (m, 2H), 3.15-2.99 (m, 2H), 2.65-2.55 (m, 1H), 2.30-2.20 (m, 1H), 1.90-1.55 (m, 8H), 1.50-1.30 (m, 7H), 1.30-1.15 (m, 8H), 1.15-1.00 (m, 9H), 0.74 (s, 3H). LCMS Rt=1.739 min (3 min chromatography), 30-90CD, purity 100%, C 24 H 42 NO2 + [M+H] + MS ESI calculated value 376, observed value 376.

[0368] Example 3. Synthesis of Compound 3 [ka] Step 1 (Compound 3). To a solution of A2 (200 mg, 0.62 mmol) in DCM (8 mL) was added TEA (314 mg, 3.11 mmol) and HATU (355 mg, 0.936 mmol) at 25 °C. After stirring at 25 °C for 30 min, aniline (92.9 mg, 0.998 mmol) was added. The mixture was stirred at 25 °C for 16 h, treated with water (8 mL), and extracted with DCM (2 × 8 mL). The organic layer was washed with brine (2 × 10 mL), dried over NaSO, filtered, and concentrated in vacuo to give the crude product, which was triturated with MeOH (12 mL) at 25 °C to give 90 mg of impure product. The impure product was recrystallized from MeCN (20 mL) at 65° C. and filtered at 25° C. to give the product, which was dissolved in MeCN (30 mL) at 65° C. and concentrated in vacuo to give compound 3 (44 mg, 49%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 7.8 Hz, 2H), 7.35-7.28 (m, 2H), 7.12-7.05 (m, 1H), 6.95 (brs, 1H), 2.35-2.22 (m, 2H), 2.06-1.98 (m, 1H), 1.89-1.60 (m, 7H), 1.52-1.23 (m, 15H), 1.20-1.04 (m, 3H), 0.75 (s, 3H). LCMS Rt=0.932min (2min chromatography), 5-95AB_220&254, purity 100%, C 26 H 38 NO2[M+H] + MS ESI calculated value 396, observed value 396.

[0369] Example 4. Synthesis of Compound 4 [ka]

[0370] Step 1 (Compound 4). To a solution of A2 (100 mg, 0.312 mmol) in DCM (5 mL) was added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25° C. The mixture was stirred at 25° C. for 30 minutes. N-methyl-1-phenylmethanamine (60.4 mg, 0.499 mmol) was added. The mixture was stirred at 25° C. for 1 hour. Water (5 mL) was added. The mixture was extracted with DCM (2 × 5 mL), washed with brine, dried over NaSO, and concentrated in vacuo to give the crude product, which was purified by preparative HPLC (Column: Xtimate C18 150 × 25 mm × 5 um; Conditions: water (0.05% ammonia hydroxide v / v)-ACN; Start B: 57; End B: 87; 100% B Retention Time (min): 2.5; Flow (ml / min): 25; Injections: 8) to give a water / CHCN solution of the product, which was concentrated in vacuo to give compound 4 (109 mg, 83%) as a solid. 1 H NMR (400MHz, CDCl3) δ 7.38-7.28 (m, 2H), 7.26-7.22 (m, 2H), 7.16-7.09 (m, 1H), 5.11-4.83 (m, 1H), 4.40-4.17 (m, 1H), 2.99-2.90 (m, 3H), 2.82-2.67 (m, 1H), 2.38-2.26 (m, 1H), 1.91-1.74 (m, 4H), 1.74-1.59 (m, 4H), 1.54-1.36 (m, 5H), 1.36-1.30 (m, 3H), 1.29-1.20 (m, 6H), 1.20-1.01 (m, 4H), 0.81 (s, 3H). LCMS Rt=1.325min (2min chromatography), 30-90AB, purity 100%, C 28 H 42 NO2[M+H] + MS ESI calculated value 424, observed value 424.

[0371] Example 5. Synthesis of Compound 5 [ka]

[0372] Step 1 (Compound 5). To a solution of A2 (100 mg, 0.312 mmol) in DCM (5 mL) was added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0. To the resulting mixture was added 100 ml of acetonitrile (468 mmol) at 25° C. The mixture was stirred at 25° C. for 1 hour. Piperidine (42.4 mg, 0.449 mmol) was added. The mixture was stirred at 25° C. for 1 hour. Water (8 mL) was added. The mixture was extracted with DCM (2×10 mL), washed with brine, dried over NaSO, and concentrated in vacuo. The residue was triturated with acetonitrile (5 mL) at 25° C. to give compound 5 (34 mg, 28%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 3.65-3.40 (m, 4H), 2.75-2.64 (m, 1H), 2.35-2.25 (m, 1H), 1.90-1.75 (m, 4H), 1.75-1.55 (m, 10H), 1.55-1.49 (m, 5H), 1.49-1.18 (m, 10H), 1.18-1.05 (m, 3H), 0.72 (s, 3H). LCMS Rt=1.896min (2.0min chromatography), 30-90CD_POS_E.M, purity 100%, C 25 H 42 NO2[M+H] + MS ESI calculated value 388, observed value 388.

[0373] Example 6. Synthesis of Compound 6 [ka]

[0374] Step 1 (Compound 6). To a solution of A2 (150 mg, 0.468 mmol) in DCM (6 mL) was added TEA (236 mg, 2.34 mmol) and HATU (266 mg, 0.7 mmol) at 25° C. After stirring at 25° C. for 30 min, 1,4-oxazepane (75.6 mg, 0.748 mmol) was added. The mixture was stirred at 25° C. for 1 h and quenched with water (8 mL). The mixture was extracted with DCM (2×8 mL). The organic layer was washed with brine (10 mL), dried over NaSO, filtered, and concentrated in vacuo to give the crude product, which was purified by preparative HPLC (Column: Waters Xbridge (150 mm × 25 mm, 5 μm)), gradient: 60-90% B (A = 10 mM NHHCO / HO, B = MeCN), flow rate: 25 mL / min) to give a solid. The solid was treated with water (5 mL), warmed to 80 °C and stirred for 2 h, filtered, and concentrated to give compound 6 (32 mg). 1 H NMR (400 MHz, CDCl3) δ 4.02-3.92 (m, 1H), 3.90-3.65 (m, 4H), 3.65-3.62 (m, 1H), 3.52-3.35 (m, 2H), 2.73-2.59 (m, 1H), 2.35-2.18 (m, 1H), 2.05-1.78 (m, 6H), 1.78-1.60 (m, 5H), 1.51-1.38 (m, 5H), 1.36-1.18(m, 9H), 1.18-1.02(m, 3H), 0.80-0.70 (s, 3H). LCMS Rt=0.863 min (2.0 min chromatography), 30-90AB, purity 100%, C 25 H 42 NO3[M+H] + MS ESI calculated value 404, measured value 404.

[0375] Example 7. Synthesis of Compound 7 [ka]

[0376] Step 1 (Compound 7). To a solution of A2 (80 mg, 0.25 mmol) in DCM (3 mL) was added TEA (125 mg, 1.24 mmol) and HATU (142 mg, 0.37 mmol) at 25° C. After stirring at 25° C. for 30 min, N-methylaniline (42.7 mg, 0.40 mmol) was added. The mixture was stirred at 25° C. for 16 h and quenched with water (5 mL). The mixture was extracted with DCM (2×4 mL). The organic phase was washed with brine (2 × 8 mL), dried over NaSO, filtered, and concentrated in vacuo to give the crude product, which was purified by preparative HPLC (Column: Xtimate C18 150 × 25 mm × 5 um; Conditions: water (0.05% ammonia hydroxide v / v)-ACN, 61% to 91% B; Gradient time (min): 10; Retention time at 100% B (min): 2.5; Flow rate (ml / min): 25) to give a solid, which was triturated with MeCN (5 mL) at 25 °C for 4 h to give compound 7 (14 mg, 14%) as a solid. 1H NMR (400 MHz, CDCl3) δ 7.50-7.40 (m, 2H), 7.40-7.30 (m, 1H), 7.15-7.05 (m, 2H), 3.26 (s, 3H), 2.50-2.40 (m, 1H), 2.15-2.00 (m, 1H), 1.90-1.60 (m, 6H), 1.50-1.20 (m, 14H), 1.10-0.75(m, 8H), 0.65-0.50 (m, 1H). LCMS Rt=1.036 min (2 min chromatography), 30-90AB, purity 100%, C 27 H 40 NO2[M+H] + MS ESI calculated value of 410.

[0377] Example 8. Synthesis of Compound 8 [ka]

[0378] Step 1 (Compound 8). To a solution of A2 (100 mg, 0.312 mmol) in DCM (4 mL) was added TEA (156 mg, 1.55 mmol) and HATU (112 mg, 0.468 mmol) at 25 °C. After stirring at 25 °C for 30 min, cyclohexaneamine (49.4 mg, 0.499 mmol) was added. The mixture was stirred at 25 °C for 16 h, quenched with water (4 mL), and extracted with DCM (2 × 4 mL). The organic layer was washed with brine (2 × 5 mL), dried over Na SO , filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography eluted with PE / EtOAc = 3 / 1 to give the impure product. The impure product was recrystallized (85 °C) from MeCN (2 mL) and water (20 mL) to give compound 8 (86 mg, 69%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 5.20-5.05 (m, 1H), 3.85-3.70 (m, 1H), 2.2 5-2.10 (m, 1H), 2.09-2.00 (m, 1H), 1.95-1.55 (m, 12H), 1.54-1.30 (m, 8H), 1.29-1.00 (m, 16H), 0.66 (s, 3H). LCMS Rt=1.176 min (2.0 min chromatography), 30-90AB, purity 100%, C 26 H 44 NO2[M+H] + MS ESI calculated value 402, measured value 402.

[0379] Example 9. Synthesis of Compound 9 [ka]

[0380] Step 1. (Compound 9). To a solution of A2 (100 mg, 0.312 mmol) in DCM (4 mL) was added TEA (156 mg, 1.55 mmol) and HATU (112 mg, 0.468 mmol) at 25 °C. After stirring at 25 °C for 30 minutes, N-methylcyclohexanamine (56.4 mg, 0.499 mmol) was added. The mixture was stirred at 25 °C for 16 hours, quenched with water (4 mL), and extracted with DCM (2 × 4 mL). The organic layer was washed with brine (2 × 5 mL), dried over Na SO , filtered, and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography eluted with PE / EtOAc = 3 / 1 to give a solid, which was lyophilized to give Compound 9 (44 mg, 34%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 4.55-4.45 (m, 0.5H), 3.80-3.70 (m, 0.5H), 2.90-2.70 (m, 3H), 2.69-2.60 (m, 1H), 2.35-2.20 (m, 1H), 1.90-1.50 (m, 15H), 1.49-1.15 (m, 18H), 1.14-1.00 (m, 3H), 0.73 (s, 3H). LCMS Rt=1.239 min (2.0 min chromatography), 30-90AB, 100% purity, C 27 H 46 NO2[M+H] + MS ESI calculated value 416, observed value 416.

[0381] Example 10. Synthesis of Compound 10 [ka]

[0382] To a solution of A2 (100 mg, 0.312 mmol) in DCM (4 mL) was added TEA (156 mg, 1.55 mmol) and HATU (112 mg, 0.468 mmol) at 25 °C. After stirring at 25 °C for 30 min, N-methyltetrahydro-2H-pyran-4-amine (57.4 mg, 0.499 mmol) was added. The mixture was stirred at 25 °C for 16 h, quenched with water (4 mL), and extracted with DCM (2 × 4 mL). The organic layer was washed with brine (2 × 5 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography eluting with PE / EtOAc (3 / 1) to give the desired compound. The compound was lyophilized to give a solid (80 mg), which was further recrystallized (85 °C) from MeCN (2 mL) and water (20 mL) to give compound 10 (66 mg, 51%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 4.85-4.70 (m, 0.5H), 4.15-3.95 (m, 2H), 3.55-3.40 (m, 1.5H), 2.90-2.70 (m, 3H), 2.69-2.60 (m, 1H), 2.35-2.20 (m, 1H), 1.90-1.60 (m, 10H), 1.59-1.16 (m, 18H),1.15-1.00 (m, 3H), 0.72 (s, 3H). LCMS Rt=1.005 min (2.0 min chromatography), 30-90AB, purity 100%, C 26 H 44 NO3[M+H] + MS ESI calculated value 418, observed value 418.

[0383] Example 11. Synthesis of Compound 11 [ka]

[0384] Step 1 (Compound 1). To a solution of A2 (100 mg, 0.312 mmol) in DCM (5 mL) was added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25 °C. After stirring at 25 °C for 30 min, pyridin-4-ylmethylamine (50.6 mg, 0.468 mmol) was added. The mixture was stirred at 25 °C for 1 h. Water (20 mL) was added. The mixture was extracted with DCM (2 × 20 mL), washed with brine (20 mL), dried over NaSO, and concentrated in vacuo to give the crude product, which was purified by flash column chromatography (0–30% EtOAc in PE) to give compound 11 (68 mg, 53%) as a solid. 1 H NMR (400MHz, CDCl3) δ 8.56 (d, J = 4.0 Hz, 2H), 7.20 (d, J = 4.0 Hz, 2H), 5.68 (br s, 1H), 4.51 (d, J = 8 Hz, 1H), 4.44 (d, J = 8 Hz, 1H), 2.22-2.15 (m, 2H), 1.91-1.79(m, 5H), 1.75-1.62 (m, 3H), 1.50-1.37 (m, 6H), 1.35-1.23 (m, 8H), 1.18-1.08 (m, 4H), 0.71 (s, 3H). LCMS Rt=1.453 min (3.0 min chromatography), 10-80AB, 100% purity, C 26 H 39 N2O2[M+H] + MS ESI calculated value 411, measured value 411.

[0385] Example 12. Synthesis of Compound 12 [ka] Step 1 (compound 12)

[0386] To a solution of A2 (100 mg, 0.312 mmol) in DCM (5 mL) was added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25 °C. After stirring at 25 °C for 30 min, pyridin-3-ylmethylamine (50.6 mg, 0.468 mmol) was added. The mixture was stirred at 25 °C for 1 h. Water (20 mL) was added. The mixture was extracted with DCM (2 × 20 mL), washed with brine (20 mL), dried over NaSO, and concentrated in vacuo to give the crude product, which was purified by flash column chromatography (0–30% EtOAc in PE) to give compound 12 (63 mg, 49%) as a solid. 1 H NMR (400MHz, CDCl3) δ 8.55-8.53 (m, 2H), 7.65 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 5.63-5.61 (m, 1H), 4.57-4.39 (m, 2H), 2.22-2.11 (m, 2H), 1.89-1.74 (m, 5H), 1.72-1.61 (m, 3H), 1.49-1.36 (m, 6H), 1.31-1.19 (m, 8H), 1.17-1.02 (m, 4H), 0.68 (s, 3H) LCMS Rt=2.016 min (4.0 min chromatography), 10-80AB, 100% purity, C 26 H 39 N2O2[M+H] + MS ESI calculated value 411, measured value 411.

[0387] Example 13. Synthesis of Compound 13 [ka]

[0388] To a solution of A2 (100 mg, 0.312 mmol) in DCM (5 mL) was added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25 °C. After stirring at 25 °C for 30 min, N-methyl-1-(pyridin-4-yl)methylamine (57.1 mg, 0.468 mmol) was added. The mixture was stirred at 25 °C for 1 h, quenched with water (20 mL), and extracted with DCM (2 × 20 mL). The organic layer was washed with brine (20 mL), dried over NaSO, and concentrated in vacuo to give the crude product, which was purified by flash silica gel chromatography (0–30% EtOAc in PE) to give compound 13 (81 mg, 61%) as a solid. 1 H NMR (400MHz, CDCl3) δ 8.59-8.54 (m, 2H), 7.15 (d, J = 4.0 Hz, 1.4H), 7.07 (d, J = 4.0 Hz, 0.6H), 5.00 (d, J = 20 Hz, 0.3H), 4.89 (d, J = 16 Hz, 0.7H), 4.37-4.26 (m, 1H), 3.03 (s, 2.2H), 2.96 (m, 0.8H), 2.81 (t, J = 12 Hz 0.8H), 2.56 (t, J = 12 Hz 0.2H) 2.34-2.26 (m, 1H), 1.81-1.74 (m, 4H), 1.72-1.61 (m, 3H), 1.52-1.21 (m, 16H), 1.13-1.11 (m, 3H), 0.79 (s, 3H) LCMS Rt=1.491 min (3.0 min chromatography), 10-80AB, 100% purity, C 27 H 41 N2O2[M+H] + MS ESI calculated value 425, measured value 425.

[0389] Example 14. Synthesis of Compound 14 [ka]

[0390] To a solution of A2 (100 mg, 0.312 mmol) in DCM (3 mL) was added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25 °C. After stirring at 25 °C for 30 min, N-methyl-1-(tetrahydro-2H-pyran-4-yl)methylamine (64.4 mg, 0.499 mmol) was added. The mixture was stirred at 25 °C for 16 h, quenched with water (15 mL), and extracted with DCM (2 × 10 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by flash silica gel chromatography (0–40% EtOAc in PE) to give compound 14 (31 mg, 23%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 4.05-3.91 (m, 2H), 3.69-3.53 (m, 1H), 3.45-3.27 (m, 2H), 3.10-3.03 (m, 2H), 3.02-2.89 (m, 2H), 2.77-2.65 (m, 1H), 2.32-2.16 (m, 1H), 1.99-1.73 (m, 5H), 1.73-1.60 (m, 4H), 1.60-1.56 (m, 1H), 1.55-1.47 (m, 2H), 1.46-1.35 (m, 6H), 1.35-1.18 (m, 10H), 1.17-1.025 (m, 3H), 0.74 (s, 3H). LCMS Rt=1.013 min (2 min chromatography), 30-90AB, purity 100%, C 27 H 46 NO3[M+H] + MS ESI calculated value 432, observed value 432.

[0391] Example 15. Synthesis of Compound 15 [ka]

[0392] To a solution of A2 (100 mg, 0.312 mmol) in DCM (3 mL) was added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25 °C. After stirring for several minutes at 25 °C, pyridin-2-ylmethylamine (53.9 mg, 0.499 mmol) was added. The mixture was stirred at 25 °C for 16 h, quenched with water (15 mL), and extracted with DCM (2 × 10 mL). The organic layer was washed with brine, dried over NaSO and concentrated in vacuo to give 110 mg of crude product, which was purified by preparative HPLC (Column: Kromasil 150 × 25 mm × 10 um; Conditions: water (0.05% ammonia hydroxide v / v)-ACN; Start B: 40; End B: 70; Gradient time (min): 8; 100% B retention time (min): 2; Flow rate (ml / min): 30; Injections: 6) and concentrated in vacuo to give compound 15 (26 mg, 24%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 8.58-8.50 (m, 1H), 7.70-7.62 (m, 1H), 7.30-7.27 (m, 1H), 7.21-7.16 (m, 1H), 6.64-6.48 (m, 1H), 4.62-4.53 (m, 2H), 2.30-2.16 (m, 1H), 2.03-1.95 (m, 1H), 1.89-1.76 (m, 4H), 1.74-1.59 (m, 4H), 1.50-1.36 (m, 6H), 1.34-1.26 (m, 7H), 1.25-0.99 (m, 5H), 0.67 (s, 3H). LCMS Rt=0.601min (2min chromatography), 30-90AB, purity 100%, C 26 H 39 N2O2[M+H] + MS ESI calculated value 411, measured value 411.

[0393] Example 16. Synthesis of Compound 16 [ka]

[0394] To a solution of A2 (100 mg, 0.312 mmol) in DCM (3 mL) was added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25° C. After stirring for 30 min at 25° C., N-methyl-1-(pyridin-3-yl)methylamine (60.9 mg, 0.499 mmol) was added. The mixture was stirred at 25° C. for 16 h, quenched with water (15 mL), and extracted with DCM (2×10 mL). The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo to give 120 mg of crude product, which was purified by preparative HPLC (column: Kromasil 150 × 25 mm × 10 μm; conditions: water (0.05% ammonia hydroxide v / v)-ACN; start B: 40; end B: 70; gradient time (min): 8; 100% B retention time (min): 2; flow rate (ml / min): 30; injections: 5) and concentrated to give compound 16 (6 mg, 5%) as a solid. NMR of the compound shows rotamers. 1 H NMR (400 MHz, CDCl3) δ 8.60-8.44 (m, 2H), 7.66-7.41 (m, 1H), 7.31-7.26 (m, 1H), 5.00-4.90 (m, 0.2H), 4.90-4.76 (m, 0.8H), 4.36-4.28 (m, 0.8H), 4.28-4.20 (m, 0.2H), 2.94 (s, 2.4H), 2.85 (s, 0.6H), 2.75-2.67 (m, 0.8H), 2.67-2.60 (m, 0.2H), 2.35-2.23 (m, 1H), 1.87-1.62 (m, 9H), 1.51-1.38 (m, 6H), 1.36-1.27 (m, 5H), 1.25-1.19 (m, 2H), 1.15-1.05 (m, 3H), 0.83-0.71 (m, 4H). LCMS Rt=0.647min (2min chromatography), 30-90AB, purity 100%, C 27 H 41 N2O2[M+H] + MS ESI calculated value 425, measured value 425.

[0395] Example 17. Synthesis of Compound 17 [ka]

[0396] Step 1 (Compound 17). To a solution of A2 (100 mg, 0.312 mmol) in DCM (3 mL) was added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25 °C. After stirring at 25 °C for 30 min, cyclohexylmethanamine (56.4 mg, 0.499 mmol) was added. The mixture was stirred at 25 °C for 16 h and treated with water (15 mL). The mixture was extracted with DCM (2 × 10 mL). The organic layer was washed with brine, dried over NaSO, filtered, and concentrated to give the crude product, which was purified by flash silica gel chromatography (0–30% EtOAc in DCM) to give crude compound 17 (23 mg, 18%) as a solid. The crude product was recrystallized from MeOH (15 mL) to give compound 17 (9 mg, 39%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 5.34-5.24 (m, 1H), 3.24-3.13 (m, 1H), 3.09-2.97 (m, 1H), 2.23-2.12 (m, 1H), 2.12-2.06 (m, 1H), 1.94-1.79 (m, 4H), 1.77-1.61 (m, 9H), 1.50-1.34 (m, 8H), 1.32-1.20 (m, 9H), 1.19-1.03 (m, 5H), 0.98-0.87 (m, 2H), 0.68 (s, 3H). LCMS Rt=1.197 min (2 min chromatography), 30-90AB, 100% purity, C 27 H 46 NO2[M+H] + MS ESI calculated value 416, observed value 416.

[0397] Example 18. Synthesis of Compound 18 [ka]

[0398] Step 1 (Compound 18). To a solution of A2 (100 mg, 0.312 mmol) in DCM (5 mL) was added TEA (213 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25 °C. After stirring at 25 °C for 30 min, N-methyl-2-phenylethanamine (63.2 mg, 0.468 mmol) was added. The mixture was stirred at 25 °C for 1 h, treated with water (20 mL), and extracted with DCM (2 × 20 mL). The organic layer was washed with brine (20 mL), dried over NaSO, filtered, and concentrated in vacuo to give the crude product, which was purified by flash silica gel chromatography (0–30% EtOAc in PE) to give compound 18 (39 mg, 29%) as a solid. 1 H NMR (400MHz, CDCl3) δ 7.37-7.26 (m, 2H), 7.26-7.12 (m, 3H), 4.00-3.83 (m, 1H), 3.42-3.23 (m, 1H), 2.94-2.97 (m, 3H), 2.87-2.76 (m, 2H), 2.67 (t, J = 8.0 Hz, 0.6H), 2.43 (t, J = 8.0 Hz, 0.4H), 2.31-2. 08 (m, 1H), 1.88-1.75 (m, 3H), 1.71-1.58 (m, 4H), 1.50-1.30 (m, 7H), 1.30-0.97 (m, 12H), 0.68-0.70 (m, 3H). LCMS Rt=3.174 min (4.0 min chromatography), 10-80AB, 100% purity, C 29 H 44 NO2[M+H] + MS ESI calculated value 438, observed value 438.

[0399] Example 19. Synthesis of Compound 19 [ka]

[0400] Step 1 (Compound 19). To a solution of A2 (100 mg, 0.312 mmol) in DCM (5 mL) was added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25 °C. The mixture was stirred at 25 °C for 30 min. 2-Phenylethanamine (37.8 mg, 0.312 mmol) was added. The mixture was stirred at 25 °C for 12 h, treated with water (20 mL), and extracted with DCM (2 × 20 mL). The organic layer was washed with brine (20 mL), dried over NaSO, and concentrated in vacuo to give the crude product, which was purified by flash silica gel chromatography (0–30% EtOAc in PE) to give compound 19 (21 mg, 16%) as a solid. 1 H NMR (400MHz, CDCl3) δ 7.33-7.28 (m, 2H), 7.25-7.18 (m, 3H), 5.25-5.20 (m, 1H), 3.66-3.60 (m, 1H), 3.51-3.42 (m, 1H), 2.82 (t, J = 8.0 Hz, 2H), 2.19-2.08 (m, 1H), 2.05-2.00 (m, 1H), 1.86-1.76 (m, 3H), 1.74-1.59 (m, 5H), 1.48-1.32 (m, 7H), 1.30-1.22 (m, 6H), 1.15-1.00 (m, 5H), 0.62 (s, 3H). LCMS Rt=2.344 min (4.0 min chromatography), 30-90AB, purity 98.4%, C 28 H 42 NO2[M+H] + MS ESI calculated value 424, observed value 424.

[0401] Example 20. Synthesis of Compound 20 [ka]

[0402] Step 1 (Compound 20). To a solution of A2 (100 mg, 0.312 mmol) in DMF (5 mL) was added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25° C. The mixture was stirred at 25° C. for 30 min. (R)-1-phenylethanamine (56.7 mg, 0.468 mmol) was added. The mixture was stirred at 25° C. for 12 h, treated with water (20 mL), and extracted with DCM (2×20 mL). The organic layer was washed with brine (20 mL), dried over NaSO, filtered, and Concentration in vacuo gave the crude product, which was purified by flash silica gel chromatography (0-30% EtOAc in PE) to give compound 20 (51 mg, 39%) as a solid. 1 H NMR (400MHz, CDCl3) δ 7.39-7.30 (m, 4H), 7.29-7.27 (m, 1H), 5.45-5.42 (m, 1H), 5.22-5.14 (m, 1H), 2.25-2.14 (m, 1H), 2.08 (t, J = 8.0 Hz, 1H), 1.97-1.91 (m, 1H), 1.89-1.79 (m, 3H), 1.77-1.62 (m, 4H), 1.50 (d, J = 4.0 Hz, 3H), 1.47-1.34 (m, 6H), 1.32-1.20 (m, 8H), 1.18-1.04 (m, 4H), 0.71 (s, 3H). LCMS Rt=3.095 min (4.0 min chromatography), 10-80AB, 100% purity, C 28 H 42 NO2[M+H] + MS ESI calculated value 424, observed value 424.

[0403] Example 21. Synthesis of Compound 21 [ka]

[0404] Step 1 (Compound 21). To a solution of A2 (100 mg, 0.312 mmol) in DMF (4 mL) was added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25 °C. After stirring at 30 °C for 30 min, (S)-N-methyl-1-phenylethanamine (63.2 mg, 0.468 mmol) was added. The mixture was stirred at 30 °C for 16 h and then treated with water (8 mL). The precipitate was collected by filtration and purified by HPLC (Waters Xbridge 150 × 25 5 μl, water (10 mM NH₄HCO₃)-ACN, gradient: 55–85% B, flow rate: 25 mL / min) to give compound 21 (40 mg, 30%) as a solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.40-7.32 (m, 2H), 7.21-7.29 (m, 3H), 6.02-5.72 (m, 1H), 3.94-3.81 (m, 1H), 3.15-2.98 (m, 3H), 2.90-2.81 (m, 1H), 2.71-2.62 (m, 3H), 2.38-2.11 (m, 1H), 1.82-1.57 (m, 8H), 1.57-1.20 (m, 10H), 1.19-1.01 (s, 7H),0.74 (s, 3H). LCMS Rt=1.174 min (2 min chromatography), 30-90AB, 100% purity, C 29 H 44 NO2[M+H] + MS ESI calculated value 438, observed value 438.

[0405] Example 22. Synthesis of Compound 22 [ka]

[0406] Step 1 (Compound 22). To a solution of A2 (100 mg, 0.312 mmol) in DMF (4 mL) was added TEA (0.213 mL, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 30 °C. After stirring at 30 °C for 30 min, N-methyl-1-(pyridin-2-yl)methanamine (60.9 mg, 0.499 mmol) was added. The mixture was stirred at 30 °C for 16 h, treated with water (8 mL), filtered, and concentrated. The crude product was purified by HPLC (Waters Xbridge 150 × 25 5 μl, water (10 mM NH₄HCO₃)-ACN, gradient: 40–70% B, flow rate: 25 mL / min) to give compound 22 (13 mg, 10%) as a solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.58-8.48 (m, 1H), 7.81-7.70 (m, 1H), 7.30-7.18 (m, 2H), 5.10-4.70 (m, 1H), 4.49-4.45 (m, 1H), 3.95-3.78 (m, 1H), 2.98-2.80 (m, 3H), 2.20-2.05 (m, 3H), 1.85-1.71 (m, 5H), 1.71-1.57 (m, 5H), 1.49-1.19 (m, 5H), 1.19-1.10 (m, 5H), 1.10-0.98 (m, 4H), 0.70 (s, 3H). LCMS Rt=0.668min (2min chromatography), 30-90AB, purity 100%, C 27 H 41 N2O2[M+H] + MS ESI calculated value 425, measured value 425.

[0407] Example 23. Synthesis of Compound 23 [ka]

[0408] Step 1 (Compound 23). To a solution of A2 (100 mg, 0.312 mmol) in DCM (2 mL) was added HATU (177 mg, 0.468 mmol), TEA (0.213 mL, 1.55 mmol), and azepane (108 mg, 1.09 mmol) at 25 °C. After stirring at 25 °C for 24 h, the mixture was poured into water (200 mL) and extracted with DCM (2 × 200 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 0:1) and lyophilized to give compound 23 (78 mg, 62%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 3.90-3.70 (m, 2H), 3.30-3.15 (m, 2H), 2.70-2.60 (m, 1H), 2.25-2.15 (m, 1H), 1.85-1.55 (m, 13H), 1.54-1.45 (m, 8H), 1.44-1.05 (m, 13H), 0.76 (s, 3H). LCMS Rt=1.121 min (2 min chromatography), 30-90AB, purity 98%, C 26 H 44 NO2[M+H] + Calculated ESI value of 402, measured value of 402.

[0409] Example 24. Synthesis of Compound 24 [ka]

[0410] Step 1 (Compound 24). To a solution of A2 (100 mg, 0.312 mmol) in DCM (2 mL) was added HATU (177 mg, 0.468 mmol), TEA (0.213 mL, 1.55 mmol), and (tetrahydro-2H-pyran-4-yl)methanamine (125 mg, 1.09 mmol) at 25 °C. After stirring at 25 °C for 12 h, the mixture was poured into water (200 mL) and extracted with DCM (2 × 200 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by column chromatography on silica (petroleum ether / ethyl acetate = 0:1) and lyophilized to give Compound 24 (48 mg, 37%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 5.40-5.30 (m, 1H), 4.05-3.90 (m, 2H), 3.40-3.30 (m, 2H), 3.25-3.15 (m, 1H) 3.10-3.00 (m, 1H), 2.15-2.05 (m, 2H), 1.90-1.55 (m, 12H), 1.50-1.00 (m, 19H), 0.67 (s, 3H). LCMS Rt=0.934min (2min chromatography), 30-90AB, purity 97%, C 26 H 44 NO3[M+H] + Calculated ESI value of 418, measured value of 418.

[0411] Example 25. Synthesis of Compound 25 [ka]

[0412] Step 1 (Compound 25) To a solution of A2 (100 mg, 0.312 mmol) in DCM (4 mL) was added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25° C. After stirring for 30 min, (R)-2-methylpiperidine (60.4 mg, 0.499 mmol) was added to the reaction mixture. The reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was triturated with EtOAc (10 mL) and n-hexane (10 mL) to give compound 25 (23 mg, 18%) as a solid. 1 H NMR (400MHz, CDCl3) δ 5.11-3.76 (m, 2H), 3.31-2.99 (m, 1H), 2.77-2.54 (m, 1H), 2.42-2.26 (m, 1H), 1.88-1.74 (m, 3H), 1.73-1.53 (m, 10H ), 1.51-1.20 (m, 17H), 1.19-1.10 (m, 5H), 0.70-0.65 (m, 3H) LCMS, Rt = 1.113 min (2.0 min chromatography), 30-90AB, purity 97.674%, C 26 H 44 NO2[M+H] + MS ESI calculated value 402, measured value 402.

[0413] Example 26. Synthesis of Compound 26 [ka]

[0414] Step 1 (Compound 26). To a solution of A2 (100 mg, 0.312 mmol) in DCM (4 mL) was added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25 °C. The mixture was stirred at 25 °C for 30 min. 1-Cyclohexyl-N-methylmethanamine (60.4 mg, 499 mmol) was added to the reaction mixture. The reaction mixture was stirred at 25 °C for 2 h. The residue was diluted with water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EtOAc = 3 / 1 to 1 / 1) to give compound 26 (76 mg, 57%) as a solid. 1 H NMR (400MHz, CDCl3) δ 3.62-3.49 (m, 1H), 3.02 (s, 1H), 2.93-2.85 (m, 2H), 2.77-2.65 (m, 1H), 2.32-2.19 (m, 1H), 1.88-1.58 (m, 14H), 1.50-1.23 (m, 15H), 1.23-0.81 (m, 9H), 0.73 (m, 3H). LCMS Rt=1.228 min (2.0 min chromatography), 30-90AB, purity 100%, C 28 H 48 NO2[M+H] + MS ESI calculated value 430, measured value 430.

[0415] Example 27. Synthesis of Compound 27 [ka]

[0416] Step 1 (Compound 27). To a solution of A2 (100 mg, 0.312 mmol) in DCM (4 mL) was added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25° C. The mixture was stirred at 25° C. for 30 minutes. (S)-1-Phenylethanamine (60.4 mg, 0.499 mmol) was added to the reaction mixture. The reaction mixture was stirred at 25° C. for 2 hours. The residue was diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was triturated with EtOAc (10 mL) and n-hexane (10 mL) to give compound 27 (28 mg, crude) as a solid, which was purified by HPLC (Method: Column YMC-Actus Triart C18 100×30 mm×5 um; Conditions: Water (0.05% HCl)-ACN; Start B: 60; End B: 90; Gradient time ( Further purification by HPLC (HPLC: 100% B retention time (min): 9.5; 100% B retention time (min): 2.5; flow rate (ml / min); 25) gave compound 27 (14 mg, 11%) as a solid. HNMR (400MHz, CDCl3) δ 7.36-7.29 (m, 4H), 7.26-7.23 (m, 1H), 5.52-5.46 (m, 1H), 5.19-5.10 (m, 1H), 2.23-2.05 (m, 1H), 1.87-1.59 (t, 8H), 1.51-1.28 (m, 10H), 1.28-1.00 (m, 11H), 0.58 (s, 3H) LCMS Rt=2.327in (4.0 min chromatography), 30-90AB, purity 99%, C 28 H 42 NO2[M+H] + MS ESI calculated value 424, observed value 424.

[0417] Example 28. Synthesis of Compound 28 [ka]

[0418] Step 1 (Compound 28). To a solution of A2 (100 mg, 0.312 mmol) in DCM (3 mL) was added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25 °C. The mixture was stirred at 25 °C for 30 min. (S)-2-Methylpiperidine (46.4 mg, 0.468 mmol) was added. The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over NaSO, and concentrated in vacuo to give the crude product, which was purified by flash silica gel chromatography (0–30% EtOAc in PE) to give compound 28 (18 mg, 14%) as a solid. 1 H NMR (400 MHz, DMSO-d6, t = 80 °C) δ 4.80-4.47 (m, 1H), 4.18-3.83 (m, 2H), 2.99-2.82 (m, 1H), 2.79-2.69 (m, 1H), 2.21-2.02 (m, 2H), 1.82-1.57 (m, 9H), 1.56-1.46 (m, 3H), 1.45-1.18 (m, 11H), 1.17-0.96 (m, 10H), 0.67 (s, 3H). LCMS Rt=1.123 min (2 min chromatography), 30-90AB, purity 100%, C 26 H 44 NO2[M+H] + MS ESI calculated value 402, measured value 402.

[0419] Example 29. Synthesis of Compound 29 [ka]

[0420] Step 1 (Compound 29). To a solution of A2 (100 mg, 0.312 mmol) in DCM (3 mL) was added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25 °C. After stirring at 25 °C for 30 min, tetrahydro-2H-pyran-4-amine (47.3 mg, 0.468 mmol) was added. The mixture was stirred at 25 °C for 16 h and treated with water (10 mL). The mixture was extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over NaSO, and concentrated in vacuo to give the crude product, which was purified by flash silica gel chromatography (0–5% MeOH in DCM) to give a solid. The crude residue (113 mg) was then triturated with MTBE (8 mL) at 15 °C to give compound 29 (80 mg, 71%) as a solid. This compound was dissolved in DCM (30 mL), and the solution was washed with citric acid (2 × 20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the crude product. This crude product was dissolved in MeCN / HO = 1 / 2 (30 mL), concentrated in vacuo to remove most of the MeCN, and lyophilized to give compound 29 (42 mg, 33%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 5.19-5.08 (m, 1H), 4.09-3.99 (m, 1H), 3.98-3.90 (m, 2H), 3.55-3.44 (m, 2H), 2.23-2.11 (m, 1H), 2.10-2.03 (m, 1H), 1.96-1.80 (m, 6H), 1.79-1.62 (m, 4H), 1.52-1.39 (m, 8H), 1.34-1.23 (m, 8H), 1.19-1.04 (m, 4H), 0.67(s, 3H). LCMS Rt=0.902 min (2 min chromatography), 30-90AB, purity 100%, C 25 H 42 NO3[M+H] + MS ESI calculated value 404, measured value 404.

[0421] Example 30. Synthesis of Compound 30 [ka]

[0422] Step 1 (Compound 30). To a solution of A2 (100 mg, 0.312 mmol) in DCM (3 mL) was added HATU (177 mg, 0.468 mmol) and EtN (156 mg, 1.55 mmol) at 25 °C. After stirring at 25 °C for 0.5 h, (S)-3-phenylpyrrolidine (73.4 mg, 0.499 mmol) was added. The reaction mixture was stirred at 40 °C for 10 h, treated with water (10 mL), and extracted with EtOAc (2 × 10 mL). The combined organic phase was washed with water (2 × 10 mL) and saturated brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (0–30% EtOAc in PE) to give compound 30 (31 mg, 22%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 7.37-7.29 (m, 2H), 7.28-7.21 (m, 3H), 4.14-3.68 (m, 2H), 3.59-3.27 (m, 3H), 2.61-2.49 (m, 1H), 2.39-2.16 (m, 2H), 2.11-1.91 (m, 1H), 1.89-1.64 (m, 9H), 1.49-1.31 (m, 9H), 1.29-1.24 (m, 5H), 1.15-1.02 (m, 3H), 0.85-0.78 (m, 3H). LCMS Rt=1.095 min (2 min chromatography), 30-90AB, 100% purity, C 30 H 44 NO2[M+H] + MS ESI calculated value 450, measured value 450. SFC Rt=9.574 min (15 min chromatography), IC_ETOH(DEA)_40_2.5ML_15MIN, 99% de. (Column: Chiralpak IC-3 150 x 4.6 mm ID, 3 μm; Mobile phase: 40% ethanol (0.05% DEA) in CO2. Flow rate: 2.5 mL / min. Column temperature: 40°C.

[0423] Example 31. Synthesis of Compound 31 [ka]

[0424] Step 1 (Compound 31) To a solution of A2 (100 mg, 0.312 mmol) in DCM (3 mL) was added HATU (177 mg, 0.468 mmol) and EtN (156 mg, 1.55 mmol) at 25 °C. After stirring at 25 °C for 0.5 h, (R)-3-phenylpyrrolidine (73.4 mg, 0.499 mmol) was added at 25 °C. The reaction mixture was stirred at 40 °C for 10 h and quenched with ice-water (10 mL). The aqueous phase was extracted with EtOAc (3 × 20 mL). The combined organic phase was washed with brine (2 × 10 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by HPLC (apparatus: BQ; method: column YMC-Actus Triart C18 100 × 30 mm × 5 μm; conditions: water (0.05% HCl)-ACN; gradient 80% to 100% B; gradient time (min): 9.5) to give compound 31 (8 mg, 6%) as a solid. HNMR (400MHz, CDCl3) δ 7.37-7.29 (m, 2H), 7.26-7.21 (m, 2H), 4,04-3.93 (m, 1H), 3.82-3.70 (m, 1H), 3.66-3.28 (m, 3H), 2.64-2.50 (m, 1H), 2.39-2.18 (m, 2H), 2.08-1.95 (m, 1H), 1.90-1.62 (m, 8H), 1.54-1.22 (m, 17H), 1.13-1.05 (m, 2H), 0.79 (s, 3H). LCMS Rt=1.090 min (2.0 min chromatography), 30-90AB, purity 100%; C 30 H 44 NO2[M+H] +The calculated ESI value is 450, and the measured value is 450. SFC Rt = 11.297 min (15 min chromatography), IC_ETOH(DEA)_40_2,5ML_15MIN, 100% de. (Column: Chiralpak IC-3 150 x 4.6 mm ID, 3 μm; Mobile phase: 40% ethanol (0.05% DEA) in CO2. Flow rate: 2.5 mL / min. Column temperature: 40 °C).

[0425] Example 32. Synthesis of Compound 32 [ka]

[0426] Step 1 (Compound 32). To a solution of A2 (200 mg, 0.624 mmol) in DCM (2 mL) was added HATU (355 mg, 0.936 mmol) and TEA (125 mg, 1.24 mmol). The mixture was stirred at 25° C. for 20 minutes. To the mixture was added (R)-N-methyl-1-phenylethanamine (126 mg, 0.936 mmol). The mixture was stirred at 25° C. for another 12 hours. The mixture was poured into water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (2×20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by HPLC (Xtimate C18 150 × 25 mm × 5 μm column, gradient: 64–89% B, conditions: water (0.05% HCl)-ACN, flow rate: 30 mL / min) to give compound 32 (50 mg) as a solid. Compound 32 was further purified by SFC (OD (250 mm × 30 mm, 5 μm) column, conditions: 0.1% NH₃H₂O in ETOH, gradient: 35–30%, flow rate (mL / min): 50 mL / min, 25 °C) to give compound 32 (35 mg, 13%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 7.37-7.23 (m,5H), 6.18 (q, J = 12.0 Hz, 1H), 2.82-2.54 (m, 4H), 2.39-2.26 (m, 1H), 1.90-1.61 (m, 7H), 1.56 (s, 3H), 1.50-1.20 (m, 16H), 1.16-1.05 (m, 3H), 0.81 (s, 3H). LCMS Rt=0.952 min (1.5 min chromatography), 5-95AB, 100% purity, C 29 H 44 NO2[M+H] + MS ESI calculated value 438, observed value 438.

[0427] Example 33. Synthesis of Compound 33 and Compound 34 [ka]

[0428] Step 1 (Compound 33 and Compound 34). To a solution of A2 (1 g, 3.12 mmol) in DCM (10 mL) was added HATU (1.77 g, 4.68 mmol) and TEA (1.57 g, 15.6 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 0.5 h. 1-(4-Fluorophenyl)propan-1-amine (764 mg, 4.99 mmol) was added to the reaction mixture at 25° C. The reaction mixture was stirred at 40° C. for 10 h. The reaction mixture was treated with water (20 mL). The mixture was extracted with EtOAc (2×20 mL). The combined organic phase was washed with water (2×20 mL) and brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0-25% EtOAc in PE) to give compound 33 (peak 1, 207 mg, 14%) and compound 34 (peak 2, 250 mg, 17%) as solids.

[0429] (250 mg, 0.54 mmol) was further purified by flash column (0-25% EtOAc in PE) to give 34 (150 mg) as a pale solid. The impurity 34 was purified again by SFC (Chiralcel OJ 250 × 30 5 μl), gradient: 25-25% B (A = 0.1% NH3 / HO, B = EtOH), flow rate: 60 mL / min) to give 34 (51 mg, 3%) as a solid.

[0430] Compound 33: 1 H NMR (400 MHz, CDCl3) δ 7.25-7.21 (m, 2H), 7.06-6.96 (m, 2H), 5.46-5.38 (d, J = 7.6 Hz, 1H), 4.93-4.82 (q, J = 7.2 Hz, J = 15.2 H z, 1H), 2.22-2.04 (m, 2H), 2.02-1.91 (m, 1H), 1.89-1.62 (m, 10H), 1.49-1.38 (m, 6H), 1.37-1.30 (m, 2H), 1.28-1.26 (m, 4H), 1.22-1.03 (m, 5H), 0.92-0.87 (t, J = 7.2 Hz, 3H), 0.70 (s, 3H). LCMS Rt=1.100min (2min chromatography), 30-90AB, purity 100%, C 29 H 43 FNO2[M+H] + MS ESI calculated value 456, observed value 456. SFC Rt = 3,350 min (10 min chromatography), OJ-H EtOH(DEA) 5 40 2.5 M, 100% de. (Column: ChiralCel OJ-H 150 x 4.6 mm ID, 5 µm; Mobile phase: A:CO₂ B:ethanol (0.05% DEA); Gradient: 5% to 40% B for 5.5 min, hold at 40% for 3 min, then 5% B for 1.5 min; Flow rate: 2.5 mL / min; Column temperature: 40 °C).

[0431] SFC of a mixture of compounds 33 and 34; Peak 1: Rt = 3.121 min and Peak 2: Rt = 3.372 min (10 min chromatography). Conditions: OJ-H_EtOH(DEA)_5_40_2.5M (Column: ChiralCel OJ-H 150 x 4.6 mm ID, 5 µm. Mobile phase: A:CO2, B:ethanol (0.05% DEA). Gradient: 5% to 40% B for 5.5 min, hold at 40% for 3 min, then 5% B for 1.5 min. Flow rate: 2.5 mL / min. Column temperature: 40 °C).

[0432] compound 34 1 H NMR (400 MHz, CDCl3) δ 7.25-7.21 (m, 2H), 7.04-6.96 (m, 2H), 5.49-5.41 (d, J = 8 Hz, 1H), 4.89-4.81 (q, J = 7.6 Hz, J = 15.2 Hz, 1H), 2.22-2.07 (m, 2H), 1.88-1.61 (m, 10H), 1.49-1.29 (m, 7H), 1.28-1.23 (m, 5H), 1.22-0.94 (m, 6H), 0.92-0.84 (t, J = 7.2 Hz, 3H), 0.50 (s, 3H). LCMS Rt=1.085min (2min chromatography), 30-90AB, purity 100%, C 29 H 43 FNO2[M+H] + MS ESI calculated value 456, observed value 456. SFC Rt = 3.116 min (10 min chromatography), OJ-H EtOH(DEA) 5 40 2.5 M, 100% de. (Column: ChiralCel OJ-H 150 x 4.6 mm ID, 5 µm; Mobile phase: A:CO₂ B:Ethanol (0.05% DEA); Gradient: 5% to 40% B for 5.5 min, hold at 40% for 3 min, then 5% B for 1.5 min; Flow rate: 2.5 mL / min; Column temperature: 40 °C).

[0433] Example 34. Synthesis of Compound 35 [ka]

[0434] Step 1 (A3): To a solution of A2 (1 g, 3.12 mmol) in toluene (20 mL), 1,2-di(pyridin-2-yl)disulfane (1.37 g, 6.24 mmol) and triphenylphosphine (1.63 g, 6.24 mmol) were added. The mixture was stirred at 25° C. for 16 hours. The reaction mixture was directly purified by silica gel chromatography (PE / EtOAc=5 / 1) to give A3 (750 mg, 58%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 8.62-8.61 (m, 1H), 7.74-7.70 (m, 1H), 7.6 0 (d, J = 8Hz, 1H), 7.28-7.27 (m, 1H), 2.73 (t, J = 8 Hz, 1H), 2.26-2.20 (m, 2H), 1.89-1.71 (m, 7H), 1.49-1.27 (m, 10H), 1.26-1.24 (m, 4H), 1.19-1.03 (m, 4H), 0.75 (s, 3H).

[0435] Step 2 (Compound 35). To a solution of A3 (100 mg, 0.242 mmol) in DCM (3 mL) was added AgOTf (62.1 mg, 0.242 mmol) followed by 1,2,3,4-tetrahydroquinoline (48.2 mg, 0.363 mmol) at 25° C. The mixture was stirred at 25° C. for 16 h. The reaction mixture was filtered and the residue was washed with DCM (15 mL). The combined organic layers were washed with 1 M HCl (10 mL), brine (30 mL), dried over NaSO, filtered, and concentrated in vacuo to give compound 35 (125 mg, crude) as an oil. The crude product was purified by HPLC (Column: YMC-Actus Triart C18 100 × 30 mm × 5 μm; Conditions: water (0.05% HCl)-CAN; Start B: 80; End B: 100; Gradient time (min): 10; 100% B retention time (min): 1; Flow rate (ml / min): 25.0) to give Compound 35 (4 mg, 4%) as a solid. LCMS Rt=1.126 min (2 min chromatography), 30-90AB, purity 100%, C 29 H 42 NO2[M+H] + MS ESI calculated value 436, observed value 436. 1 H NMR (400 MHz, CDCl3) δ 7.24-7.04 (m, 4H), 4.44-4.19 (m, 1H), 3.40-3.10 (m, 2H), 2.82-2.58 (m, 2H), 2.37-2.01 (m, 3H), 1.86-1.70 (m, 7H), 1.41-1.23 (m, 13H), 1.08-0.92 (m, 5H), 0.74 (s, 4H).

[0436] Example 35. Synthesis of Compound 36 [ka]

[0437] Step 1 (Compound 36). To a solution of A3 (150 mg, 0.362 mmol) in DCM (3 mL) was added AgOTf (93 mg, 0.362 mmol) followed by 4-amino-3-methylbenzonitrile (71.7 mg, 0.543 mmol) at 25° C. After stirring the reaction at 25° C. for 1 h, the reaction mixture was filtered and the residue was washed with DCM (15 mL). The combined organic layers were washed with 1 M HCl (10 mL), brine (50 mL), dried over NaSO, filtered, and concentrated in vacuo to give compound 36 (130 mg, crude) as an oil. The crude compound 36 (125 mg, 0.2869 mmol) was purified by HPLC (Method: Column: YMC-Actus Triart C18 100 × 30 mm × 5 μm; Conditions: Water (0.05% HCl)-ACN Start B: 70; End B: 100; Gradient time (min): 10; 100% B retention time (min): 1; Flow rate (ml / min): 25.) to give compound 36 (8 mg, 6%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 8.38-8.31 (m, 1H), 7.55-7.48 (m, 1H), 7.46 (s, 1H), 6.96 (s, 1H), 2.40-2.22 (m, 5H), 2.09-1.99 (m, 1H), 1.88-1.75 (m, 6H), 1.50-1.39 (m, 7H), 1.35-1.24 (m, 9H), 1.17-1.06 (m, 3H), 0.75 (s, 3H). LCMS Rt=1.081 min (2 min chromatography), 30-90AB, purity 100%, C 28 H 39 N2O2[M+H] + MS ESI calculated value 435, measured value 435.

[0438] Example 36. Synthesis of Compound 37 [ka]

[0439] Step 1 (Compound 37). To a solution of A3 (150 mg, 0.362 mmol) in DCM (3 mL) was added AgOTf (93 mg, 0.362 mmol), followed by 2-amino-5-fluorobenzonitrile (73.9 mg, 0.543 mmol) at 25° C. After stirring the reaction at 25° C. for 1 h, the reaction mixture was filtered and the residue was washed with DCM (15 mL). The combined organic layers were washed with 1 M HCl (10 mL), brine (50 mL), dried over NaSO, filtered, and concentrated in vacuo to give compound 37 (136 mg, crude) as an oil. The crude compound 37 (125 mg, 0.2869 mmol) was purified by HPLC (Method: Column: YMC-Actus Triart C18 100 × 30 mm × 5 μm; Conditions: Water (0.05% HCl)-ACN Start B: 70; End B: 100; Gradient time (min): 10; 100% B retention time (min): 1; Flow rate (ml / min): 25.0) to give compound 37 (2 mg, 2%) as a solid. LCMS Rt=1.044 min (2 min chromatography), 30-90AB, 100% purity, C 27 H 34 FNO[M+H-HO] + MS ESI calculated value 421, observed value 421. 1 H NMR (400 MHz, CDCl3) δ 8.48-8.40 (m, 1H), 7.49-7.42 (s, 1H), 7.33-7.27 (m, 2H), 2.44-2.35 (m, 1H), 2.34-2.21 (m, 1H), 2.19-2.07 (m, 1H), 1.93-1.71 (m, 6H), 1.52-1.37 (m, 7H), 1.36-1.21 (m, 9H), 1.19-1.01 (m, 3H), 0.75 (s, 3H).

[0440] Example 37. Synthesis of Compound 38 [ka] The synthesis of B1 is disclosed in WO2014 / 169833.

[0441] Step 1 (Compound 38). To a solution of B1 (200 mg, 0.503 mmol) in DMF (5 mL) was added aniline (56.2 mg, 0.604 mmol) and TEA (151 mg, 1.50 mmol) at 25 °C under N2. The mixture was stirred at 25 °C for 18 h to give a yellow solution. The mixture was poured into saturated aqueous LiCl (50 mL) and extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with saturated brine (2 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give a pale solid, which was purified by preparative HPLC (column: YMC-Actus Triart C18 150 × 30 5 μl; conditions: water (0.05% HCl)-ACN; gradient 46% to 76% B; gradient time (min): 8). The mixture was purified and freeze-dried to give compound 38 (42.0 mg, 21%) as a pale solid. 1 H NMR (400 MHz, CDCl3) δ 7.25-7.15 (m, 2H), 6.72-6.68 (m, 1H), 6.62-6.55 (m, 2H), 4.72-4.65(m, 1H), 4.00-3.85(m, 2H), 3.52-3.45 (m, 1H), 2.60-2.53 (m, 1H), 2.30-2.15 (m, 1H), 2.00-1.55 (m, 8H), 1.50-1.20(m, 14H), 1.15-0.90 (m, 3H), 0.65(s, 3H). LCMS Rt=1.160 min (2.0 min chromatography), 30-90AB, 100% purity, C 27 H 40 NO2[M+H] + MS ESI calculated value 410, measured value 410.

[0442] Example 38. Synthesis of Compound 39 [ka]

[0443] Step 1 (Compound 39). To a solution of B1 (200 mg, 0.503 mmol) in DMF was added N-methylaniline (64.6 mg, 0.604 mmol) and TEA (151 mg, 1.50 mmol) at 25 °C under N. The mixture was stirred at 25 °C for 18 h to give a yellow solution. The mixture was poured into aqueous LiCl (50 mL, 1N) and extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with saturated brine (2 × 50 mL), dried over anhydrous NaSO, filtered, and concentrated to give a pale solid. The crude product was purified by pre-HPLC (column: YMC-Actus Triart C18 150 × 30 5 μm; conditions: water (0.05% HCl)-ACN; gradient 46% to 76% B; gradient time (min): 8) to give the compound (50 mg, containing residual ammonium salt) as a pale solid. The product was dissolved in DCM (5 mL) and washed with aqueous NaHCO (10 mL). The aqueous layer was extracted with DCM (2 × 10 mL). The combined organic phases were dried over anhydrous NaSO, filtered, and concentrated to give compound 39 (21 mg, 10%) as a pale solid. 1 H NMR (400 MHz, CDCl3) δ 7.25-7.15 (m, 2H), 6.72-6.68 (m, 1H), 6.62-6.55 (m, 2H), 4.10-3.98 (m, 2H), 3.00 (s, 3H), 2.62-2.53 (m, 1H), 2.18-2.07 (m, 1H), 1.98-1.92 (m, 1H), 1.85-1.55 (m, 7H), 1.50-1.35(m, 7H), 1.35-1.18 (m, 8H), 1.18-1.00 (m, 3H), 0.67(s, 3H). LCMS Rt=1.182 min (2.0 min chromatography), 30-90AB, purity 100%, C 28 H 42 NO2[M+H] + MS ESI calculated value 424, observed value 424.

[0444] Example 39. Synthesis of Compound 40 [ka]

[0445] Step 1 (Compound 40). To a solution of B1 (100 mg, 0.251 mmol) in DMF (5 mL) was added 4-fluoroaniline (33.4 mg, 0.301 mmol) and TEA (76.1 mg, 0.753 mmol) at 25 °C under N. The mixture was stirred at 25 °C for 16 hours to give a yellow solution. The mixture was concentrated to give a pale solid. The solid was purified by preparative HPLC (column: Phenomenex Gemini 150 × 25 mm × 10 μm; conditions: water (0.05% HCl)-ACN; gradient 60% to 100% B; gradient time (min): 10) to give compound 40 (25 mg, 23%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 6.95-6.86 (m, 2H), 6.68-6.60 (m, 2H), 4.00-3.85 (m, 2H), 2.58-2.52 (m, 1H), 2.26-2.12 (m, 1H), 1.95-1.55 (m, 9H), 1.50-1.14 (m, 15H), 1.14-0.96 (m, 3H), 0.63(s, 3H). LCMS Rt=0.962 min (1.5 min chromatography), 5-95AB, 100% purity, C 27 H 39 FNO2[M+H] + MS ESI calculated value 428, observed value 428.

[0446] Example 40. Synthesis of Compound 41 [ka]

[0447] Step 1 (Compound 41). To a solution of B1 (100 mg, 0.251 mmol) in DMF (5 mL) was added 3-fluoroaniline (33.4 mg, 0.301 mmol) and TEA (76.1 mg, 0.753 mmol) at 25 °C under N. The mixture was stirred at 25 °C for 16 hours to give a yellow solution. The mixture was concentrated to give a pale solid. The solid was purified by preparative HPLC (column: Phenomenex Gemini 150 × 25 mm × 10 μm; conditions: water (0.05% HCl)-ACN; gradient 60% to 100% B; gradient time (min): 10) to give Compound 41 (7 mg, 7%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 7.13-7.05 (m, 1H), 6.45-6.33 (m, 2H), 6.30-6.22 (m, 1H), 3.96-3.83(m, 2H), 2.58-2.52 (m, 1H), 2.26-2.12 (m, 1H), 2.02-1.55 (m, 10H), 1.50-1.14 (m, 14H), 1.14-0.93 (m, 3H), 0.65 (s, 3H). LCMS Rt=0.988min (1.5min chromatography), 5-95AB, 100% purity, C 27 H 39 FNO2[M+H] + MS ESI calculated value 428, observed value 428.

[0448] Example 41. Synthesis of Compound 42 [ka]

[0449] Step 1 (Compound 42). To a suspension of diisopropylethylamine (42.1 mg, 0.326 mmol) in DMF (5 mL) was added 3-fluoro-N-methylaniline (62.7 mg, 0.502 mmol) at 25 °C under N2. After stirring at 25 °C for 30 min, a solution of B1 (100 mg, 0.251 mmol) in DMF (5 mL) was added. The mixture was stirred at 40 °C for 16 h to give a yellow solution. The mixture was concentrated to give the product as a pale yellow oil (150 mg, crude), which was purified by HPLC (column: Phenomenex Gemini C18 250 × 50 10 u; conditions: water (0.05% ammonia hydroxide v / v)-ACN; gradient 80% to 90% B; gradient time (min): 8) to give Compound 42 (11 mg, 10%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 7.13-7.05 (m, 1H), 6.40-6.20(m, 3H), 4.08-3.98(m, 2H), 2.98 (s, 3H), 2.60-2.50 (m, 1H), 2.22-2.08 (m, 1H), 2.05-1.95 (m, 1H), 1.90-1.50 (m, 7H), 1.50-1.35(m, 7H), 1.35-1.20 (m, 8H), 1.20-1.00(m, 3H), 0.67(s, 3H). LCMS Rt=1.197 min (2.0 min chromatography), 30-90AB, 100% purity, C28H41FNO2 [M+H] + MS ESI calculated value 442, observed value 442.

[0450] Example 42. Synthesis of Compound 43 [ka]

[0451] Step 1 (Compound 43). To a solution of B1 (100 mg, 0.251 mmol) in DMF (5 mL) was added 4-fluoro-N-methylaniline (37.6 mg, 0.301 mmol) and TEA (76.1 mg, 0.753 mmol) at 25 °C under N. The mixture was stirred at 25 °C for 16 hours to give a yellow solution. The reaction was concentrated to give a pale solid. The solid was purified by preparative HPLC (column: Phenomenex Gemini 150 × 25 mm × 10 μm; conditions: water (0.05% HCl)-ACN; gradient 60% to 100% B; gradient time (min): 10) to give Compound 43 (30 mg, 27%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 6.95-6.86 (m, 2H), 6.58-6.47 (m, 2H), 4.05-3.95 (m, 2H), 2.97 (s, 3H), 2.60-2.52 (m, 1H), 2.18-2.07 (m, 1H), 1.96-1.51 (m, 9H), 1.51-1.02 (m, 17H), 0.66 (s, 3H). LCMS Rt=0.971 min (1.5 min chromatography), 5-95AB, 100% purity, C 28 H 41 FNO2[M+H] + MS ESI calculated value 442, observed value 442.

[0452] Example 43. Synthesis of Compound 44 [ka] The synthesis of C1 is disclosed in WO2015 / 180679.

[0453] Step 1 (C2). Liquid bromine (6.55 g, 41.0 mmol) was slowly added to vigorously stirred aqueous sodium hydroxide solution (54.6 mL, 3 M, 164 mmol) at 0 °C. Once all the bromine had dissolved, the mixture was diluted with cold dioxane (15 mL) and slowly added to a stirred solution of C1 (5 g, 13.7 mmol) in dioxane (20 mL) and water (15 mL). The homogeneous yellow solution slowly became colorless, and a white precipitate formed. The reaction mixture was stirred at 25 °C for 5 h. The remaining oxidant was quenched by the addition of aqueous NaSO (30 mL), and the mixture was then heated to 80 °C until the solid material dissolved. The solution was acidified with HCl (3 M, 40 mL), causing a solid to precipitate. The solid was filtered and washed with water (3×100 mL) to give a solid, which was dried in vacuo to give C2 (5 g, crude) as a solid. 1 H NMR (400 MHz, CDCl3) δ 11.89 (br s, 1H), 4.13 (br s, 1H), 3.46 (q, J=7.0 Hz, 2H), 3.32-3.26 (m, 2H), 2.29 (t, J = 9.2 Hz, 1H), 1.99-1.89 (m, 2H), 1.78-1.46 (m, 7H), 1.41-1.14 (m, 11H), 1.11 (t, J = 7.0 Hz, 3H), 1.07-0.91 (m, 3H), 0.62 (s, 3H).

[0454] Step 2 (Compound 44). To a solution of C2 (100 mg, 0.274 mmol) in DCM (3 mL) was added HATU (156 mg, 0.411 mmol) and EtN (137 mg, 1.36 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 0.5 h. 1,2,3,4-Tetrahydroisoquinoline (54.7 mg, 0.411 mmol) was added to the reaction mixture at 25° C. The reaction mixture was stirred at 25° C. for 1 h. The reaction mixture was quenched with ice water (10 mL). The aqueous phase was extracted with EtOAc (3×20 mL). The combined organic phase was washed with brine (2×10 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by HPLC (apparatus: BQ; method: column YMC-Actus Triart C18 100 × 30 mm × 5 μm; conditions: water (0.05% HCl)-ACN; start B: 80 end B: 100; gradient time (min): 8; 100% B retention time (min): 2; flow rate (ml / min): 25; injections: 8) to give compound 44 (65.0 mg, 50%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 7.26-7.02 (m, 4H), 4.88-4.65 (m, 2H), 4.00-3.65 (m, 2H), 3.56-3.36 (m, 4H), 2.90-2.66 (m, 3H), 2.35 (m, 1H), 1.80-1.56 (m, 9H), 1.56-0.96 (m, 17H), 0.76-0.72 (m, 3H). LCMS Rt=0.971 min (1.5 min chromatography), 5-95AB, 100% purity, C 31 H 46 NO3[M+H] + MS ESI calculated value 480, measured value 480.

[0455] Example 44. Synthesis of Compound 45 and Compound 46 [ka]

[0456] Step 1 (D2): To a solution of commercially available D1 (10 g, 46.6 mmol) in THF (60 mL) was added Lawesson's reagent (9.42 g, 23.3 mmol). The mixture was stirred at 20 °C for 1 h. The mixture was concentrated in vacuo. To the residue was added NaHCO (120 mL, saturated), and the mixture was stirred at 20 °C for 1 h. The mixture was filtered, and the precipitate was washed with water (2 × 50 mL) and dried in vacuo to give D2 (9.5 g, 89%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 7.49 (br, 2H), 4.65 (dd, J = 3.6, 8.4 Hz, 1H), 3.70-3.30 (m, 2H), 2.70-1.80 (m, 4H), 1.46 (s, 9H). LCMS Rt=0.814 min (2.0 min chromatography), 10-80, 100% purity, C5H 11 N2S[M+H-Me2C=CH2-CO2] + MS ESI calculated value 131, observed value 131.

[0457] Step 2 (D3). To a solution of D2 (5 g, 21.7 mmol) in DME (250 mL) was added KHCO (17.3 g, 173 mmol) and bromoacetone (8.91 g, 65.1 mmol). The mixture was stirred at 20 °C for 1 h. To the mixture was added pyridine (14.5 g, 184 mmol) and TFAA (18.2 g, 86.8 mmol) at 0 °C. The mixture was stirred at 20 °C for 16 h. To the mixture was added NaHCO (150 mL, saturated), and the mixture was concentrated in vacuo. The residue was dissolved in EtOAc (200 mL), washed with water (200 mL), dried over NaSO, filtered, concentrated in vacuo, and purified by flash column (0–20% EtOAc in PE) to give D3 (3.6 g, 62%) as an oil. 1H NMR (400 MHz, CDCl3) δ 6.73 (s, 1H), 5.38-5.00 (m, 1H), 3.69-3.37 (m, 2H), 2.41 (s, 3H), 2.38-2.11 (m, 2H), 2.00-1.82 (m, 2H), 1.54-1.29 (m, 9H). LCMS Rt=1.059 min (2.0 min chromatography), 10-80, purity 97.4% (220 nm), C 13 H 21 N2O2S[M+H] + MS ESI calculated value 269, observed value 269.

[0458] Step 3 (D4). To D3 (3.6 g, 13.4 mmol) was added HCl / dioxane (20 mL, 4 M). The mixture was stirred at 20 °C for 15 min. The mixture was concentrated in vacuo. The residue was dissolved in water (25 mL) and washed with MTBE (20 mL). The aqueous phase was basified with NaCO (saturated) to pH = 10. The mixture was extracted with MTBE (2 × 20 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo to give 5-methyl-2-(pyrrolidin-2-yl)thiazole D4 (1 g, 90% purity, 40% yield) as a light brown oil. 1 H NMR (400 MHz, CDCl3) δ 6.73 (s, 1H), 4.52 (dd, J = 6.4 Hz, 8. 0 Hz, 1H), 3.18-3.10 (m, 1H), 3.10-3.00 (m, 1H), 2.40 (s, 3H), 2.34-2.22 (m, 1H), 2.21-2.04 (br, 1H), 2.00-1.75 (m, 5H). LCMS Rt=0.544 min (2.0 min chromatography), 0-30AB, 100% purity, C8H 13 N2S[M+H] + MS ESI calculated value 169, observed value 169.

[0459] Step 4 (Mixture of Compound 45 and Compound 46). To a solution of C2 (200 mg, 0.548 mmol) in DCM (5 mL) was added HATU (312 mg, 0.822 mmol) and EtN (275 mg, 2.73 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 0.5 h. 5-Methyl-2-(pyrrolidin-2-yl)thiazole (D4, 138 mg, 0.822 mmol) was added to the reaction mixture at 25 °C. After stirring at 25 °C for 10 h, the reaction mixture was quenched with ice water (20 mL) and extracted with DCM (3 × 5 mL). The combined organic phase was dried over anhydrous NaSO, filtered, and concentrated to give a racemic mixture of Compound 45 and Compound 46 (200 mg) as an oil, which was further purified. LCMS Rt=0.902 min (1.5 min chromatography), 5-95AB, purity 65%, C 30 H 47 N2O3S[M+H] + MS ESI calculated value 515, measured value 515.

[0460] Step 5 (Compounds 45 and 46): An impure racemic mixture of Compounds 45 and 46 (200 mg, 0.388 mmol) was separated by SFC (column: AD (250 mm × 30 mm, 5 μm), gradient: 45–45% B (A = 0.05% NH / HO, B = MeOH), flow rate: 60 mL / min) to give Compound 45 (Peak 1, 33 mg, 16%) and Compound 46 (Peak 2, 43 mg, 21%) as solids. SFC Peak 1: Rt = 5.407 min and Peak 2 Rt = 7.126 min (10 min chromatography), AD_3_IPA_DEA_5_40_25ML. (Column: Chiralpak AD-3 150 x 4.6 mm ID, 3 um. Mobile phase: A:CO2, B:isopropanol (0.05% DEA). Gradient: 5% to 40% B for 5 min and hold at 40% for 2.5 min, then 5% B for 2.5 min. Flow rate: 2.5 mL / min. Column temperature: 35°C).

[0461] compound 45 1H NMR (400 MHz, CDCl3) δ 6.83-6.67 (m, 1H), 5.49-5.22 (m, 1H), 3.79-3.59 (m, 2H), 3.56-3.37 (m, 4H), 2.75-2.68 (m, 1H), 2.60-2.53 (m, 1H), 2.50-2.37 (m, 3H), 2.32-1.90 (m, 6H), 1.88-1.65 (m, 7H), 1.49-1.25 (m, 9H), 1.22-1.19 (m, 3H), 1.18-0.99 (m, 4H), 0.98-0.93 (m, 1H), 0.83 (s, 3H). LCMS Rt=1.261 min (2.0 min chromatography), 10-80AB, 100% purity, C 30 H 47 N2O3S[M+H] + MS ESI calculated value 515, measured value 515.

[0462] SFC Rt=5.390 min (10 min chromatography), AD_3_EtOH_DEA_5_40_25ML, 100% de. (Column: Chiralpak AD-3 150 x 4.6 mm ID, 3 μm. Mobile phase: A:CO2, B:iso-propanol (0.05% DEA). Gradient: 5% to 40% B for 5 min, hold at 40% for 2.5 min, then 5% B for 2.5 min. Flow rate: 2.5 mL / min. Column temperature: 35°C).

[0463] compound 46 1 H NMR (400 MHz, CDCl3) δ 6.80-6.64 (m, 1H), 5.60-5.35 (m, 1H), 3.86-3.73 (m, 1H), 3.64-3.34 (m, 5H), 2.85-2.55 (m, 2H), 2.49-2.36 (m, 3 H), 2.33-2.15 (m, 3H), 2.08-1.94 (m, 2H), 1.89-1.58 (m, 8H), 1.51-1.33 (m, 7H), 1.32-1.02 (m, 10H), 0.74 (s, 3H). LCMS Rt=1.271 min (2.0 min chromatography), 10-80AB, 100% purity, C 30 H 47 N2O3S[M+H] + MS ESI calculated value 515, measured value 515.

[0464] SFC Rt=7.166 min (10 min chromatography), AD_3_EtOH_DEA_5_40_25ML, 99.8% DEA. (Column: Chiralpak AD-3 150 x 4.6 mm ID, 3 μm. Mobile phase: A:CO2, B:isopropanol (0.05% DEA). Gradient: 5% to 40% B for 5 min, hold at 40% for 2.5 min, then 5% B for 2.5 min. Flow rate: 2.5 mL / min. Column temperature: 35°C).

[0465] Example 45. Synthesis of Compound 47 [ka]

[0466] To a solution of C2 (200 mg, 0.548 mmol) in DMF (5 mL) were added HATU (312 mg, 0.822 mmol) and EtN (275 mg, 2.73 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 0.5 h. 4-Fluoro-2,6-dimethylaniline (114 mg, 0.822 mmol) was added to the reaction mixture at 25 °C. After stirring at 50 °C for 10 h, the reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic phase was washed with 3% aqueous LiCl (2 × 20 mL), dried over anhydrous NaSO, filtered, concentrated, and purified by flash silica gel chromatography (0–40% EtOAc in PE) to give 50 mg of impure product, which was purified by preparative HPLC (column: YMC-Actus Triart C18 100 × 30 mm × 5 um), gradient: 80–100% B (A = water (0.05% HCl), B = MeCN), flow rate: 25 mL / min) to give compound 47 (12 mg, 24%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 6.82-6.72 (m, 2H), 6.58-6.48 (m, 1H), 3.61-3.33 (m, 4H), 2.88-2.59 (m, 1H), 2.39-2.31 (m, 1H), 2.20 (s, 6H), 2.13-2.05 (m, 1H), 1.94-1.58 (m, 9H), 1.52-1.35 (m, 7H), 1.30-1.06 (m, 9H), 0.81 (s, 3H). LCMS Rt=1.313 min (2.0 min chromatography), 10-80AB, 100% purity, C 30 H 45 FNO3[M+H] + MS ESI calculated value 486, observed value 486.

[0467] Example 46. Synthesis of Compound 48 and Compound 49 [ka]

[0468] Step 1 (Compound 48). To a solution of C2 (200 mg, 0.548 mmol) in DCM (5 mL) was added HATU (312 mg, 0.822 mmol) and EtN (275 mg, 2.73 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 0.5 h. (R)-4-(1-aminoethyl)benzonitrile (120 mg, 0.822 mmol) was added to the reaction mixture at 25° C. After stirring at 25° C. for 10 h, the reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3×5 mL). The combined organic phase was washed with saturated brine (2 × 10 mL), dried over anhydrous NaSO, filtered, and concentrated to give a residue, which was purified by flash silica gel chromatography (0–60% EtOAc in PE) and preparative TLC (PE:EtOAc = 1:1) to give compound 48 (150 mg, 55%) as a solid. 1 H NMR (400 MHz, CDCl3) 7.65-7.59 (m, 2H), 7.44-7.37 (m, 2H), 5.52-5.44 (m, 1H), 5.22-5.11 (m, 1H), 3.57-3.49 (m, 2H), 3.48-3.38 (m, 2H), 2.74 (s, 1H), ,2.21-2.07 (m, 2H), 1.95-1.88 (m, 1H), 1.87-1.62 (m, 7H), 1.51-1.32 (m, 9H), 1.32-1.24 (m, 3H), 1.23-1.18 (m, 4H), 1.17-1.02 (m, 4H), 0.68 (s, 3H). LCMS Rt=4.765 min (7.0 min chromatography), 10-80AB, 100% purity, C 31 H 45 N2O3[M+H] + MS ESI calculated value 493, observed value 493.

[0469] Step 2 (E1): To a solution of compound 48 (120 mg, 0.275 mmol) in DCM (3 mL) was added imidazole (198 mg, 2.91 mmol) and TMSCl (236 mg, 2.18 mmol) at 20° C. After stirring at 20° C. for 30 minutes, the mixture was quenched with water (10 mL) and extracted with DCM (2×5 mL). The combined organic layer was washed with water (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give E1 (137 mg, crude) as a solid. 1 H NMR (400 MHz, CDCl3) δ 7.65-7.59 (m, 2H), 7.44-7.37 (m, 2H), 5.52-5.44 (m, 1H), 5.22-5.11 (m, 1H), 3.54-3.32 (m, 4H),2.22-2.09 (m, 2H), 1.97-1.88 (m, 1H), 1.81-1.65 (m, 7H), 1.52-1.41 (m, 6H), 1.38-1.16 (m, 11H), 1.10-0.97 (m, 3H), 0.69 (s, 3H), 0.11 (s, 9H).

[0470] Step 3 (E2): To a solution of E1 (137 mg, 0.242 mmol) in DMF (3 mL) was added NaH (96.6 mg, 2.42 mmol, 60% purity) at 0 °C. After stirring at 0 °C under N for 10 min, MeI (515 mg, 3.63 mmol) was added slowly at 0 °C under N. After stirring at this temperature for 10 min, the reaction mixture was diluted with water (10 ml). The mixture was quenched with HCl (10 mL) and extracted with EtOAc (2×5 mL). The combined organic phases were washed with LiCl (10 mL, 3% aqueous solution), dried over NaSO, filtered, and concentrated to give E2 (140 mg, crude) as a brown oil. 1H NMR (400 MHz, CDCl3) δ 7.71-7.57 (m, 2H), 7.41-7.34 (m, 2H), 6.21-6.12 (m, 0.84 H), 5.41-5.28 (m, 0.16 H), 3.55-3.31 (m, 4H), 2.78-2.62 (m, 4H), 2.37-2.25 (m, 1H), 1.82-1.65 (m, 9H), 1.53-1.39 (m, 8H), 1.36-1.29 (m, 5H), 1.15-1.04 (m, 6H), 0.91-0.75 (m, 3H), 0.10 (s, 9H).

[0471] Step 4 (Compound 49). A solution of E2 (140 mg, 0.241 mmol) in TBAF (2.4 mL, 2.4 mmol, 1 M in THF) was heated at 30 °C for 30 min. The mixture was quenched with 50% NH Cl (10 mL) and extracted with EtOAc (2 × 5 mL). The combined organic phases were washed with brine (2 × 10 mL), dried over Na SO , filtered, concentrated, and purified by flash silica gel chromatography (0–15% EtOAc in PE) to give compound 49 (18 mg, 15%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 7.71-7.57 (m, 2H), 7.41-7.34 (m, 2H), 6.21-6.12 (m, 0.84 H), 5.41-5.28 (m, 0.16 H), 3.59-3.33 (m, 4H), 2.79-2.56 (m, 5H), 2.36-2.21 (m, 1H), 1.85-1.61 (m, 8H), 1.52-1.33 (m, 10H), 1.32-1.23 (m, 3H), 1.22-1.17 (m, 4H), 1.16-1.06 (m, 3H), 0.91-0.75 (m, 3H). LCMS Rt=1.126 min (2.0 min chromatography), 30-90AB, purity 100%, C 32 H 47 N2O3[M+H] +MS ESI calculated value 507, measured value 507.

[0472] Example 47. Synthesis of Compound 50 [ka] Step 1 (Compound 50). To a solution of C2 (100 mg, 0.274 mmol) in DCM (3 mL) was added HATU (156 mg, 0.411 mmol) and TEA (137 mg, 1.36 mmol) at 25 °C. After stirring for 10 min at 25 °C, piperidine (34.9 mg, 0.411 mmol) was added to the reaction mixture at 25 °C. The reaction mixture was stirred at 25 °C for 1 h and quenched with ice-water (10 mL). The aqueous phase was extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine (2 × 10 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by HPLC (instrument: BQ; method: column chromatography). Purification by YMC-Actus Triart C18 100 x 30 mm x 5 um; Conditions: water (0.05% HCl)-ACN; Start B: 80; End B: 100; Gradient time (min): 8; 100% B hold time (min): 2; Flow rate (ml / min): 25; Injections: 7) gave compound 50 (78 mg, 66%) as a solid. 1 H NMR (400 MHz, CDCl) δ 3.65-3.38 (m, 8H), 2.75-2.65 (m, 2H), 2.38-2.25 (m, 1H), 1.86-1.56 (m, 12H), 1.50-1.00 (m, 19H), 0.72 (s, 3H). LCMS Rt = 1.104 min (2 min chromatography), 30-90AB, 100% purity, C 27 H 46 NO3[M+H] + MS ESI calculated value 432, observed value 432.

[0473] Example 48. Synthesis of Compound 51 [ka]

[0474] Step 1 (Compound 51). To a solution of C2 (100 mg, 0.274 mmol) and 4-fluoro-2-methylaniline (41.0 mg, 0.328 mmol) in DCM (3 mL) was added EDCI (78.7 mg, 0.411 mmol) and DMAP (16.7 mg, 0.137 mmol). The mixture was stirred at 30 °C for 3 h. The reaction mixture was quenched with water (5 mL) and extracted with DCM (2 × 5 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by HPLC (Column: Xtimate C18 150 × 25 mm × 5 μm; Conditions: water (0.05% HCl)-ACN; Gradient: 60% to 90% B; Flow rate: 30 mL / min) to give Compound 51 (23 mg, 18%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 7.78-7.72 (m, 1H), 6.92-6.85 (m, 2H), 6.72 (s, 1H), 3.58-3.50 (m, 2H), 3.48-3.38 (m, 2H), 2.35-2.21 (m, 5H), 2.09-2.02 (m, 1H), 1.88-1.71 (m, 6H), 1.69-1.62 (m, 2H), 1.52-1.34 (m, 8H), 1.31-1.09 (m, 9H), 0.77 (s, 3H). LCMS Rt=1.123 min (2.0 min chromatography), 30-90AB, purity 100% (HPLC), C 29 H 43 FNO3[M+H] + MS ESI calculated value 472, observed value 472.

[0475] Example 49. Synthesis of Compound 52 [ka]

[0476] Step 1 (C3): To a solution of C2 (1 g, 2.74 mmol) in toluene (20 mL), 1,2-di(pyridin-2-yl)disulfane (1.2 g, 5.48 mmol) and triphenylphosphine (1.43 g, 5.48 mmol) were added. The mixture was stirred at 25 °C for 16 hours. The reaction mixture was purified by silica gel chromatography (PE / EtOAc = 5 / 1) to give C3 (800 mg, 64%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 8.62-8.61 (m, 1H), 7.74-7.70 (m, 1H), 7.60 (d, J = 8 Hz, 1H), 7.28-7.27 (m, 1H), 3.53 (q, J = 7 Hz, 2H), 3.43 (q, J = 9.3 Hz, 2H), 2.79-2.68 (m, 2H), 2.28-2.16 (m, 2H), 1.94-1.60 (m, 8H), 1.50-1.33 (m, 7H), 1.30-1.03 (m, 9H), 0.74 (s, 3H).

[0477] Step 2 (Compound 52). To a solution of C2 (100 mg, 0.218 mmol) in DCM (3 mL) was added AgOTf (56 mg, 0.218 mmol) followed by 1,2,3,4-tetrahydroquinoline (43.5 mg, 0.327 mmol) at 25 °C. After stirring the reaction at 25°C for 1 hour, the reaction mixture was filtered and the filter cake was washed with DCM (15 mL). The combined organic layers were washed with 1M HCl (10 mL), brine (50 mL), dried over NaSO, filtered, and concentrated in vacuo to give an oil (95 mg), which was purified by HPLC (column: YMC-Actus Triart C18 100 x 30 mm x 5 um; conditions: water (0.05% HCl)-ACN; gradient: 85% B to 100% B; flow rate: 25 mL / min) to give compound 52 (16 mg, 17%) as a solid. 1H NMR (400 MHz, CDCl3) δ 7.23-7.02 (m, 4H), 4.42-4.22 (m, 1H), 3.54-3.48 (m, 2H), 3.43-3.34 (m, 2H), 3.32-3.12 (m, 2H), 2.79-2.59 (m, 3H), 2.34-2.20 (m, 1H), 2.13-2.03 (m, 1H), 1.82-1.63 (m, 6H), 1.52-1.35 (m, 6H), 1.34-1.24 (m, 4H), 1.22-1.14 (m, 5H), 1.10-0.83 (m, 5H), 0.73 (s, 3H). LCMS Rt=1.190 min (2.0 min chromatography), 30-90AB, purity 100%, C 31 H 46 NO3[M+H] + MS ESI calculated value 480, measured value 480.

[0478] Example 50. Synthesis of Compound 53 [ka]

[0479] Step 1 (Compound 53). To a solution of C3 (100 mg, 0.218 mmol) in DCM (3 mL) was added AgOTf (56 mg, 0.218 mmol) followed by 2-amino-5-fluorobenzonitrile (44.5 mg, 0.327 mmol) at 25° C. After the reaction was stirred at 25° C. for 1 h, the reaction mixture was filtered and the filter cake was washed with DCM (15 mL). The combined organic layers were washed with 1M HCl (10 mL), brine (50 mL), dried over NaSO, filtered, and concentrated in vacuo to give an oil (90 mg), which was purified by HPLC (column: YMC-Actus Triart C18 100 × 30 mm × 5 um; conditions: water (0.05% HCl)-ACN; gradient: 75% B to 100% B; flow rate: 25 mL / min) to give compound 53 (18 mg, 20%) as a solid. 1H NMR (400 MHz, CDCl3) δ 8.46-8.40 (m, 1H), 7.45 (s, 1H), 7.34-7.26 (m, 2H), 3.57-3.50 (m, 2H), 3.48-3.38 (m, 2H), 2.71 (s, 1H), 2.43-2.36 (m, 1H), 2.33-2.21 (m, 1H), 2.16-2.09 (m, 1H), 1.92-1.72 (m, 6H), 1.66-1.59 (m, 2H), 1.52-1.38 (m, 7H), 1.34-1.25 (m, 3H), 1.24-1.17 (m, 4H), 1.16-1.07 (m, 2H), 0.75 (s, 3H). 19 F NMR (400 MHz, CDCl3) δ -116.43 (s). LCMS Rt=1.094 min (2.0 min chromatography), 30-90AB, purity 100%, C 29 H 40 FN2O3[M+H] + MS ESI calculated value 483, observed value 483.

[0480] Example 51. Synthesis of Compound 54 [ka]

[0481] Step 1 (Compound 54). To a solution of C3 (100 mg, 0.218 mmol) in DCM (3 mL) was added AgOTf (56 mg, 0.218 mmol) followed by 4-amino-3-methylbenzonitrile (43.2 mg, 0.327 mmol) at 25° C. After the reaction was stirred at 25° C. for 1 h, the reaction mixture was filtered and the filter cake was washed with DCM (15 mL). The combined organic layers were washed with 1M HCl (10 mL), brine (50 mL), dried over NaSO, filtered, and concentrated in vacuo to give an oil (93 mg), which was purified by HPLC (column: YMC-Actus Triart C18 100 × 30 mm × 5 um; conditions: water (0.05% HCl)-ACN; gradient: 75% B to 100% B; flow rate: 25 mL / min) to give compound 54 (12 mg, 13%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.4 Hz, 1H), 7.53-7.48 (m, 1H), 7.46 (s, 1H), 6.96 (s, 1H), 3.57-3.50 (m, 2H), 3.47-3.38 (m, 2H), 2.75 (s, 1H), 2.40-2.24 (m, 5H), 2.06-1.99 (m, 1H), 1.91-1.72 (m, 6H), 1.68-1.60 (m, 2H), 1.50-1.36 (m, 7H), 1.32-1.18 (m, 6H), 1.18-1.04 (m, 3H), 0.75 (s, 2H), 0.77-0.72 (m, 1H). LCMS Rt=1.129 min (2.0 min chromatography), 30-90AB, purity 100%, C 30 H 43 N2O3[M+H] + MS ESI calculated value 479, observed value 479.

[0482] Example 52. Synthesis of Compound 55 [ka]

[0483] Step 1 (F2). To a solution of commercially available F1 (20 g, 80.2 mmol) in DCM (200 mL) was added 2,2-dimethoxyethanamine (8.43 g, 80.2 mmol), HOBt (14 g, 104 mmol), EDCI (19.9 g, 104 mmol), and TEA (40.5 g, 401 mmol) at 25 °C. The mixture was stirred at 25 °C for 19 h. The mixture was filtered. The filtrate was washed with water (2 × 150 mL), brine (2 × 150 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give F2 (27 g, crude) was obtained as an oil.

[0484] Step 2 (F3) To a solution of F2 (17 g, 50.5 mmol) in acetone (200 mL) was added aqueous HCl (151 mL, 3 M) at 25 °C. The mixture was stirred at 25 °C for 16 h. The mixture was extracted with EtOAc (3 × 250 mL). The organic phase was washed with water (3 × 600 mL), saturated NaHCO3 (3 × 500 mL), brine (3 × 450 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give F3 (5.57 g) as an oil.

[0485] Step 3 (F4). To a stirred solution of F3 (5.57 g, 19.1 mmol) and perchloroethane (9.04 g, 38.2 mmol) in dichloromethane (200 mL) was added PPh3 (10 g, 38.2 mmol). The mixture was stirred at 0 °C for 15 min, Et3N (5.51 mL, 38.2 mmol) was then added, and the mixture was stirred at 25 °C for 18 h. The mixture was washed with water (2 × 150 mL), brine (2 × 150 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by flash silica gel chromatography (0–65% EtOAc in PE) to give F4 (2.7 g, 52%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.75-7.45 (s, 1H), 7.10-6.98 (m, 2H), 5.20-4.95 (m, 3H), 3.75-3.45 (m, 2H), 2.40-2.20 (m, 3H), 2.00-1.95 (m, 1H)

[0486] Step 4 (F5). To a solution of F4 (1.3 g, 4.77 mmol) in AcOH (5 mL) was added HBr (10 mL, 35% in AcOH) at 25° C. The mixture was stirred at 25° C. for 4 h. MTBE (25 mL) was added, producing a solid. The mixture was filtered. The filter cake was washed with MTBE (15 mL) and dried in vacuo at 50° C. to give F5 (800 mg, 77%) as a solid. 1 H NMR (400 MHz, methanol-d4) δ 8.03 (s, 1H), 7.27 (s, 1H), 5.05-4.80 (m, 1H), 3.60-3.45 (m, 2H), 2.60-2.55 (m, 1H), 2.45-2.35 (m, 1H), 2.31-2.20 (m, 2H)

[0487] Step 5 (Compound 55). To a solution of C2 (200 mg, 0.548 mmol) in DCM (5 mL) was added HATU (312 mg, 0.822 mmol) and EtN (276 mg, 2.73 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 0.5 h. (S)-2-(pyrrolidin-2-yl)oxazole hydrobromide (180 mg, 0.822 mmol) was added to the reaction mixture at 25 °C for 18 h. The reaction mixture was diluted with EtOAc (30 mL), washed with water (50 mL), brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated to give a crude material. The crude material was purified by silica gel chromatography using PE / EtOAc = 0 / 1-1 / 1 to give compound 55 (200 mg) as a pale solid. Compound 55 was further purified by pre-HPLC (conditions: water (0.05% ammonia hydroxide v / v)-ACN, column: Phenomenex Gemini C18 250 × 50 mm × 10 μm, gradient time: 8 min) to give compound 55 (100 mg, 50%) as a solid. 1 H NMR (400 MHz, CDCl3) δ 7.62-7.50 (m, 1H), 7.14-6.99 (m, 1H), 5.27-5.11 (m, 1H), 3.93-3.29 (m, 7H), 2.77-2.49 (m, 2H), 2.31-1.99 (m, 5H), 1.84-1.60 (m, 8H), 1.49-1.32 (m, 7H), 1.25-1.17 (m, 6H), 1.16-1.03 (m, 3H), 0.85-0.76 (m, 3H) LCMS Rt=0.977 min (2.0 min chromatography), 30-90AB, purity 100%; C 29 H 45 N2O4[M+H] + MS ESI calculated value 485, measured value 485. SFC Rt=1.488min (3.0min chromatography), AD-H_3U M_4_5_40_4ML_3MIN.M, 100% DEA. (Column: Chiralpak AD-3 50 x 4.6 mm ID, 3 μm; Mobile phase: A:CO2 B:isopropanol (0.05% DEA); Gradient: Hold at 5% for 0.2 min, then 5% to 40% B for 1.4 min and 40% B for 1.05 min, then 5% B for 0.35 min; Flow rate: 4 mL / min. Column temperature: 40°C).

[0488] Example 53. Synthesis of Compound 56 and Compound 57 [ka]

[0489] Step 1 (G2). To a solution of titanium(IV) isopropoxide (2.51 g, 8.67 mmol) in methanamine (611 mg, 2 M in MeOH) was added commercially available 1-(4-fluorophenyl)propan-1-one (G1, 1 g, 6.57 mmol) at 25 °C. The mixture was stirred at 25 °C for 12 hours. To the mixture was added NaBH (248 mg, 6.57 mmol). The mixture was stirred at 25 °C for 10 minutes. The mixture was poured into saturated NH Cl (10 mL) and water (10 mL). The reaction mixture was filtered and washed with PE (3 × 10 mL). The filtrate was concentrated to give G2 (400 mg, 36%) as an oil, which was used in the next step without further purification.

[0490] Step 2 (Mixture of Compounds 56 and 57). To a solution of C2 (200 mg, 0.548 mmol) in DCM (5 mL) was added HATU (312 mg, 0.822 mmol) and EtN (276 mg, 2.73 mmol) at 25° C. After stirring at 25° C. for 0.5 h, 1-(4-fluorophenyl)-N-methylpropan-1-amine (G2, 137 mg, 0.822 mmol) was added to the reaction mixture at 25° C. The reaction mixture was stirred at 40° C. for 10 h. The residue was quenched with ice water (10 mL). The aqueous phase was extracted with EtOAc (3×20 mL). The combined organic phase was washed with saturated brine (2 × 10 mL), dried over anhydrous NaSO, filtered, and concentrated to give a mixture of compounds 56 and 57 (300 mg, crude) as a solid, which was further purified as described in step 3 below.

[0491] Step 3 (Compound 56 and Compound 57): A mixture of Compounds 56 and 57 (300 mg, crude) was purified by silica gel chromatography eluted with PE: EtOAc = 3 / 1 to give Compound 56 (35 mg, 12%) as a solid and Compound 57 (46 mg, 15%) as a solid.

[0492] compound 56 1 H NMR (400 MHz, CDCl3) δ 7.28-7.21 (m, 2H), 7.08-6.94 (m, 2H), 5.97-5.85 (m, 0.9H), 5.08-4.99 (m, 0.1H), 3.57-3.49 (m, 2H), 3.47-3.36 (m , 2H), 2.74-2.64 (m, 4H), 2.39-2.25 (m, 1H), 2.01-1.90 (m, 1H), 1.88-1.60 (m, 10H), 1.51-1.05 (m, 17H), 0.96 (t, J=7.28, 3H), 0.94 (s, 0.4H), 0.80 (s, 2.6H). LCMS Rt=5.531 min (7 min chromatography), 10-80AB, purity 98%, C 32 H 49FNO3[M+H] + MS ESI calculated value 514, measured value 514. SFC Rt=4.251 min (10 min chromatography), OD_3_EtOH_DEA_5_40_25ML, 98% de. (Column: Chiralcel OD-3 150 x 4.6 mm ID, 3 μm. Mobile phase: A:CO2 B:ethanol (0.05% DEA). Gradient: 5%-40% B for 5 min, hold at 40% for 2.5 min, then 5% B for 2.5 min. Flow rate: 2.5 mL / min. Column temperature: 35°C).

[0493] compound 57 1 H NMR (400 MHz, CDCl3) δ 7.29-7.23 (m, 2H), 7.19-7.15 (m, 0.2H), 7.08-6.96 (m, 1.8H), 5.94-5.75 (m, 0.9H), 5.02-4.94 (m, 0.1H), 3.57-3.48 (m, 2H), 3.47-3.36 (m, 2H), 2.79-2.64 (m, 5H), 2.36-2.10 (m, 1H), 2.03-1.96 (m, 1H), 1.86-1.61 (m, 8H), 1.50-0.97 (m, 18H), 0.95-0.88 (m, 3H), 0.87 (s, 0.4H), 0.80 (s, 2.6H). LCMS Rt=5.485 min (7 min chromatography), 10-80AB, purity 98%, C 32 H 49 FNO3[M+H] + MS ESI calculated value 514, measured value 514. SFC Rt=2.890 min (10 min chromatography), OD_3_EtOH_DEA_5_40_25 mL, 99% de. (Column: Chiralcel OD-3 150 x 4.6 mm ID, 3 μm. Mobile phase: A:CO2, B:ethanol (0.05% DEA). Gradient: 5% to 40% B for 5 min, hold at 40% for 2.5 min, then 5% B for 2.5 min. Flow rate: 2.5 mL / min. Column temperature: 35°C).

[0494] Example 54. Synthesis of Compound 58 and Compound 59 [ka]

[0495] Step 1 (H2). To a solution of commercially available H1 (3 g, 19.7 mmol) in MeOH (100 mL) was added AcONH4 (15.1 g, 196 mmol) and NaBH3CN (6.18 g, 98.4 mmol) at 20 °C. The mixture was stirred at 20 °C for 19 h. Water (100 mL) was added, and a solid formed. The mixture was filtered. The filtrate was extracted with EtOAc (2 × 80 mL). The combined organic phases were washed with water (2 × 100 mL), brine (2 × 80 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give H2 (2.15 g, 71%) as a pale yellow oil, which was used in the next step without further purification.

[0496] Step 2 (Compound 58 and Compound 59). To a solution of C2 (200 mg, 0.548 mmol) in DCM (5 mL) was added HATU (312 mg, 0.822 mmol) and TEA (276 mg, 2.73 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 0.5 h. 1-(4-Fluorophenyl)propan-1-amine H2 (125 mg, 0.822 mmol) was added to the reaction mixture at 25 °C. The reaction mixture was stirred at 40 °C for 10 h. The residue was quenched with ice water (10 mL). The aqueous phase was extracted with EtOAc (3 × 20 mL). The combined organic phase was washed with saturated brine (2 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluted with PE: EtOAc = 3 / 1 to give compound 58 (100 mg, 37%, Rf = 0.6 in PE / EtOAc = 3 / 1) as a solid and compound 59 (100 mg, 37% Rf = 0.5 in PE / EtOAc = 3 / 1) as a solid.

[0497] Compound 58 (100 mg) was further purified twice by silica gel chromatography followed by SFC (Column: Chiralcel OJ-3 150 × 4.6 mm ID, 3 μm Mobile phase: A:CO2B:ethanol (0.05% DEA) Gradient: 5% to 40% B for 5 min, hold at 40% for 2.5 min, then 5% B for 2.5 min Flow rate: 2.5 mL / min Column temperature: 35 °C) to give compound 58 (23 mg, yield) as a solid.

[0498] Compound 59 (100 mg) was purified twice by SFC (Column: Chiralcel OJ-3 150 × 4.6 mm ID, 3 μm Mobile phase: A:CO2B:ethanol (0.05% DEA) Gradient: 5% to 40% B for 5 min, hold at 40% for 2.5 min, then 5% B for 2.5 min Flow rate: 2.5 mL / min Column temperature: 35 °C) to give compound 59 (17 mg, yield) as a solid.

[0499] compound 58 1 H NMR (400 MHz, CDCl3) δ 7.26-7.21 (m, 2H), 7.05-6.98 (m, 2H), 5.46-5.40 (m, 1H), 4.88 (q, J=7.53Hz, 1H), 3.53 (q, J=7.03Hz, 2H), 3.43 (q, J=9.54, 2H), 2.73 (s, 1H), 2.22-2.03 (m, 2H), 1.99-1.92 (m, 1H), 1.87-1.61 (m, 9H), 1.51-1.02 (m, 17H), 0.89 (t, J=7.53, 3H), 0.70 (s, 3H). LCMS Rt=1.334 min (2.0 min chromatography), 10-80AB, 100% purity, C 31 H 47 FNO3[M+H] + MS ESI calculated value 500, measured value 500. SFC Rt=2.890 min (10 min chromatography), OJ_3_EtOH_DEA_5_40_25ML, 98% de. (Column: Chiralcel OJ-3 150 x 4.6 mm ID, 3 μm. Mobile phase: A:CO2, B:ethanol (0.05% DEA). Gradient: 5%-40% B for 5 min, hold at 40% for 2.5 min, then 5% B for 2.5 min. Flow rate: 2.5 mL / min. Column temperature: 35°C).

[0500] compound 59 1 H NMR (400 MHz, CDCl3) δ 7.25-7.21 (m, 2H), 7.04-6.96 (m, 2H), 5.49-5.40 (m, 1H), 4.85 (q, J=7.36Hz, 1H), 3.53 (q, J=6.86Hz, 2H), 3.42 (q, J=9.12Hz, 2H), 2.72 (s, 1H), 2.22-2.07 (m, 2H), 1.86-1.70 (m, 7H), 1.68-1.62 (m, 2H), 1.49-0.95 (m, 18H), 0.88 (t, J=7.4Hz, 3H), 0.49 (s, 3H). LCMS Rt=1.322 min (2.0 min chromatography), 10-80AB, 100% purity, C 31 H 47 FNO3[M+H] + MS ESI calculated value 500, actual Measurement: 500. SFC Rt=2.668 min (10 min chromatography), OJ_3_EtOH_DEA_5_40_25ML, 95% de. (Column: Chiralcel OJ-3 150 x 4.6 mm ID, 3 μm. Mobile phase: A:CO2, B:ethanol (0.05% DEA). Gradient: 5%-40% B for 5 min, hold at 40% for 2.5 min, then 5% B for 2.5 min. Flow rate: 2.5 mL / min. Column temperature: 35°C).

[0501] Example 55. Synthesis of Compound 60 [ka]

[0502] Step 1 (I2). To a solution of commercially available I1 (20 g, 80.2 mmol) in DCM (200 mL) was added 2,2-dimethoxyethanamine (8.43 g, 80.2 mmol), HOBt (14 g, 104 mmol), EDCI (19.9 g, 104 mmol), and TEA (40.5 g, 401 mmol) at 25 °C. The mixture was stirred at 25 °C for 19 h. The mixture was filtered and concentrated in vacuo to give the crude product, which was purified by flash silica gel chromatography (0–70% EtOAc in PE) to give I2 (20 g, 74%) as an oil. 1 H NMR (400 MHz, CDCl3) δ 7.32 (s, 5H), 5.20-5.00 (m, 2H), 3.55-3.20 (m, 10H), 2.40-1.80 (m, 5H)

[0503] Step 2 (I3). To a solution of I2 (9.9 g, 29.4 mmol) in acetone (200 mL, 29.4 mmol) was added HCl (176 mL, 1 M) at 25 °C. The mixture was stirred at 25 °C for 18 h. The reaction mixture was combined with another batch prepared from 100 mg of I2. The reaction mixture was extracted with ethyl acetate (3 × 150 mL). The combined organic phases were washed with water (3 × 300 mL) and brine (2 × 200 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give I3 (2.4 g, crude) as an oil.

[0504] Step 3 (I4). To a stirred solution of I3 (2.4 g, 8.26 mmol) and perchloroethane (3.9 g, 16.5 mmol) in dichloromethane (100 mL) was added PPh3 (4.32 g, 16.5 mmol). The mixture was stirred at 0 °C for 15 min. TEA (1.66 g, 16.5 mmol) was then added, and the mixture was stirred at 25 °C for 18 h. The mixture was washed with water (2 × 80 mL), brine (2 × 80 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by flash silica gel chromatography (0–65% EtOAc in PE) to give I4 (630 mg, 32%) as an oil, which was used directly for the next step.

[0505] Step 4 (I5). Dissolve I4 (530 mg, 1.94 mmol) in AcOH (3 mL). To the solution was added HBr (6 mL, 35% in AcOH) at 25° C. The mixture was stirred at 25° C. for 2 h. MTBE (15 mL) was added, producing a solid. The mixture was filtered. The filter cake was washed with MTBE (15 mL) and dried in vacuo at 50° C. to give I5 (430 mg, crude) as a solid. 1 H NMR (400 MHz, methanol-d4) δ 8.05 (s, 1H), 7.28 (s, 1H), 5.05-4.85 (m, 2H), 3.60-3.45 (m, 2H), 2.60-2.50 (m, 1H), 2.45-2.35 (m, 1H), 2.30-2.21 (m, 2H)

[0506] Step 5 (Compound 60) To a solution of 2 (200 mg, 0.548 mmol) in DCM (5 mL) was added HATU (313 mg, 1.30 mmol) and EtN (276 mg, 2.73 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 0.5 h. (R)-2-(Pyrrolidin-2-yl)oxazole hydrobromide I5 (180 mg, 0.822 mmol) was added to the reaction mixture at 25 °C. The reaction mixture was stirred at 25 °C for 18 h. The reaction mixture was diluted with EtOAc (30 mL), washed with water (50 mL), brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated to give the crude product, which was purified by silica gel chromatography using PE:EtOAc = 0:1 to 1:1 to give compound 60 (190 mg) ...

Claims

[Claim 1] Coma.

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