BACKGROUND

Brain excitability is defined as the level of arousal of an animal, a continuum that ranges from coma to convulsions, and is regulated by various neurotransmitters. In general, neurotransmitters are responsible for regulating the conductance of ions across neuronal membranes. At rest, the neuronal membrane possesses a potential (or membrane voltage) of approximately −70 mV, the cell interior being negative with respect to the cell exterior. The potential (voltage) is the result of ion (K+, Na+, Cl−, organic anions) balance across the neuronal semipermeable membrane. Neurotransmitters are stored in presynaptic vesicles and are released under the influence of neuronal action potentials. When released into the synaptic cleft, an excitatory chemical transmitter such as acetylcholine will cause membrane depolarization, e.g., a change of potential from −70 mV to −50 mV. This effect is mediated by postsynaptic nicotinic receptors which are stimulated by acetylcholine to increase membrane permeability to Na+ions. The reduced membrane potential stimulates neuronal excitability in the form of a postsynaptic action potential.

In the case of the GABA receptor complex (GRC), the effect on brain excitability is mediated by GABA, a neurotransmitter. GABA has a profound influence on overall brain excitability because up to 40% of the neurons in the brain utilize GABA as a neurotransmitter. GABA regulates the excitability of individual neurons by regulating the conductance of chloride ions across the neuronal membrane. GABA interacts with its recognition site on the GRC to facilitate the flow of chloride ions down an electrochemical gradient of the GRC into the cell. An intracellular increase in the levels of this anion causes hyperpolarization of the transmembrane potential, rendering the neuron less susceptible to excitatory inputs, i.e., reduced neuron excitability. In other words, the higher the chloride ion concentration in the neuron, the lower the brain excitability and level of arousal.

It is well-documented that the GRC is responsible for the mediation of anxiety, seizure activity, and sedation. Thus, GABA and drugs that act like GABA or facilitate the effects of GABA (e.g., the therapeutically useful barbiturates and benzodiazepines (BZs), such as Valium®) produce their therapeutically useful effects by interacting with specific regulatory sites on the GRC. Accumulated evidence has now indicated that in addition to the benzodiazepine and barbiturate binding site, the GRC contains at least one distinct site for interaction with neuroactive steroids. See, e.g., Lan, N. C. et al.,Neurochem. Res. (1991) 16:347-356.

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 hormonal steroids progesterone and deoxycorticosterone, respectively. The ability of these steroid metabolites to alter brain excitability was recognized in 1986 (Majewska, M. D. et al.,Science232:1004-1007 (1986); Harrison, N. L. et al.,J Pharmacol. Exp. Ther.241:346-353 (1987)).

New and improved neuroactive steroids are needed that act as modulating agents for brain excitability, as well as agents for the prevention and treatment of CNS-related diseases. The compounds, compositions, and methods described herein are directed toward this end.

SUMMARY OF THE INVENTION

Compounds as described herein, act, in certain embodiments, as GABA modulators, e.g., effecting the GABAAreceptor in either a positive or negative manner. As modulators of the excitability of the central nervous system (CNS), as mediated by their ability to modulate GABAAreceptor, such compounds are expected to have CNS-activity.

In an aspect, provided herein is a compound of the Formula (I):


or a pharmaceutically acceptable salt thereof, wherein: each of R2, R4, R6, R7, R11a, and R11bis independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, —N(RA1)2, —NHC(═O)RA1, —S(═O)RA2, —SO2RA2, or —S(═O)2ORA1, wherein each instance of RA1is 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 RA1groups are joined to form an heterocyclic or heteroaryl ring; and RA2is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R11aand R11btogether with the carbon atom to which they are attached form a carbocyclyl, heterocyclyl, or —C(═O)—; R3is alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; each of R17aand R17bis independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, —N(RA1)2, —NHC(═O)RA1, —S(═O)RA2, —SO2RA2, or —S(═O)2ORA1, wherein at least one of R17aand R17bis not hydrogen; R19is hydrogen or alkyl (e.g., unsubstituted alkyl or substituted alkyl (e.g., —C(RC)2ORA1, wherein RCis hydrogen or alkyl)); R5is absent or hydrogen; andrepresents a single or double bond, wherein when oneis a double bond, the otheris a single bond and R5is absent.

In some embodiments, R19is hydrogen or alkyl. In some embodiments, R19is unsubstituted alkyl. In some embodiments, R19is substituted alkyl. In some embodiments, R19is —CH2OH, —CH2OCH3, —CH2OCH2CH3, or —CH2OCH(CH3)2.

In some embodiments, R2is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, or —N(RA1)2. In some embodiments, R2is hydrogen, halogen, alkyl, or —ORA1. In some embodiments, R2is hydrogen.

In some embodiments, R3is alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, R3is alkyl (e.g., substituted or unsubstituted alkyl). In some embodiments, R3is methyl and ethyl (e.g., substituted or unsubstituted alkyl).

In some embodiments, R4is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, or —N(RA1)2. In some embodiments, R4is hydrogen, halogen, alkyl, or —ORA1. In some embodiments, R4is hydrogen.

In some embodiments,represents a single bond and R5is hydrogen. In some embodiments, R5is absent, andrepresents a single or double bond, wherein when oneis a double bond, the otheris a single bond.

In some embodiments, R6is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, or —N(RA1)2. In some embodiments, R6is hydrogen, halogen, alkyl, or —ORA1. In some embodiments, R6is hydrogen.

In some embodiments, R7is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, or —N(RA1)2. In some embodiments, R7is hydrogen, halogen, alkyl, or —ORA1. In some embodiments, R7is hydrogen.

In some embodiments, R11ais hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, —N(RA1)2, or R11aand R11btogether with the carbon atom to which they are attached form —C(═O)—. In some embodiments, R11ais hydrogen, halogen, alkyl, or —ORA1. In some embodiments, R11aand R11btogether with the carbon atom to which they are attached form —C(═O)—. In some embodiments, R11aand R11bare hydrogen.

In some embodiments, each of R2, R4, R6, R7, R11a, and R11bis independently hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, or —N(RA1)2. In some embodiments, each of R2, R4, R6, R7, R11a, and R11bis independently hydrogen, halogen, alkyl, or —ORA1. In some embodiments, R2, R4, R6, R7, R11a, and R11bare hydrogen.

In some embodiments, each of R7aand R17bis independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, —SRA1, —N(RA1)2, —NHC(═O)RA1—S(═O)RA2, —SO2RA2, or —S(═O)2ORA1, wherein at least one of R17aand R17bis not hydrogen. In some embodiments, each of R17aand R17bis independently hydrogen, halogen, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, —SRA1, —N(RA1)2, —NHC(═O)RA1—S(═O)RA2, —SO2RA2, or —S(═O)2ORA1, wherein at least one of R17aand R17bis not hydrogen.

In some embodiments, R17ais halogen, cyano, nitro, alkyl, carbocyclyl, heterocyclyl, —ORA1, —SRA1, —N(RA1)2, —NHC(═O)RA1, —S(═O)RA2, or —SO2RA2. In some embodiments, R17ais halogen, nitro, alkyl, carbocyclyl, heterocyclyl, —ORA1, —SRA1, —N(RA1)2, —NHC(═O)RA1, —S(═O)RA2, or —SO2RA2. In some embodiments, R17ais halogen, cyano, nitro, alkyl, —ORA1, —SRAu, or —N(RA1)2.

In an aspect, provided herein is a compound of the Formula (II):


or a pharmaceutically acceptable salt thereof, wherein: each of R2, R4, R6, R7, R11a, and R11bis independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, —N(RA1)2, —NHC(═O)RA1, —NHC(═O)ORA1, —S(═O)RA2, —SO2RA2, or —S(═O)2ORA1, wherein each instance of RA1is 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 RA1groups are joined to form an heterocyclic or heteroaryl ring; and RA2is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R11aand R1btogether with the carbon atom to which they are attached form a carbocyclyl, heterocyclyl, or —C(═O)— group; R3is hydrogen, alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; A is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, —ORA1, —SRA1, or —N(RA1)2; R19is hydrogen or alkyl (e.g., unsubstituted alkyl (e.g., —CH3) or substituted alkyl (e.g., —C(RC)2ORA1, wherein RCis hydrogen or alkyl)); R5is absent or hydrogen; and
represents a single or double bond, wherein when oneis a double bond, the otheris a single bond and R5is absent.

In some embodiments, A is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, or —ORA1.

In some embodiments, R19is hydrogen. In some embodiments, R19is alkyl (e.g., substituted or unsubstituted alkyl). In some embodiments, R19is —CH3or —CH2CH3. In some embodiments, R19is —C(RC)2ORA1. In some embodiments, R19is —CH2OH, —CH2OCH3, —CH2OCH2CH3, or —CH2OCH(CH3)2.

In some embodiments, R2is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, or —N(RA1)2. In some embodiments, R2is hydrogen, halogen, alkyl, or —ORA1. In some embodiments, R2is hydrogen.

In some embodiments, R3is alkyl (e.g., substituted or unsubstituted alkyl). In some embodiments, R3is methyl and ethyl (e.g., substituted or unsubstituted methyl, substituted or unsubstituted ethyl).

In some embodiments, R4is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, or —N(RA1)2. In some embodiments, R4is hydrogen, halogen, alkyl, or —ORA1. In some embodiments, R4is hydrogen.

In some embodiments,represents a single bond and R5is hydrogen. In some embodiments, R5is absent, andrepresents a single or double bond, wherein when oneis a double bond, the otheris a single bond.

In some embodiments, R6is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, or —N(RA1)2. In some embodiments, R6is hydrogen, halogen, alkyl, or —ORA1. In some embodiments, R6is hydrogen.

In some embodiments, R7is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, or —N(RA1)2. In some embodiments, R7is hydrogen, halogen, alkyl, or —ORA1. In some embodiments, R7is hydrogen.

In some embodiments, R11ais hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, —N(RA1)2, or R11aand R11btogether with the carbon atom to which they are attached form —C(═O)—. In some embodiments, R11ais hydrogen, halogen, alkyl, or —ORA1. In some embodiments, R11aand R11btogether with the carbon atom to which they are attached form —C(═O)—. In some embodiments, R11aand R11bare hydrogen.

In some embodiments, each of R2, R4, R6, R7, R1a, and R11bis independently hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, or —N(RA1)2. In some embodiments, each of R2, R4, R6, R7, R11a, and R11bis hydrogen, halogen, alkyl, or —ORA1. In some embodiments, each of R2, R4, R6, R7, R11a, and R11bis hydrogen.

In some embodiments, the compound of Formula (II) is a compound of the Formula (II-a) or (II-b):



In some embodiments, the compound of Formula (II) is a compound of the Formula (II-c):


wherein:
each of R21aand R21bis independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, —N(RA1)2, —NHC(═O)RA1, —NHC(═O)ORA1, —S(═O)RA2, —SO2RA2, or —S(═O)2ORA; or R21aand R21btogether 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, —ORA1, —SRA1, or —N(RA1)2; and n is an integer selected from 1, 2, and 3.

In some embodiments, the compound of Formula (II) is a compound of the Formula (II-d):



In an aspect, provided herein is a compound of the Formula (III):


wherein:
or a pharmaceutically acceptable salt thereof, wherein: each of R2, R4, R6, R7, R11a, and R11bis independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA—, —N(RA1)2, —NHC(═O)RA1, —NHC(═O)ORA1, —S(═O)RA2, —SO2RA2, or —S(═O)2ORA1, wherein each instance of RA1is 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 RA1groups are joined to form an heterocyclic or heteroaryl ring; and RA2is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R11aand R11btogether 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, —ORA1, —SRA1, or —N(RA1)2; R19is unsubstituted alkyl; R5is absent or hydrogen; andrepresents a single or double bond, wherein when oneis a double bond, the otheris a single bond and R5is absent.

In an aspect, provided herein is a compound of the Formula (IV):


or a pharmaceutically acceptable salt thereof, wherein: each of R2, R4, R6, R7, R11a, and R11bis independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, —N(RA1)2, —NHC(═O)RA1, —NHC(═O)ORA1, —S(═O)RA2, —SO2RA2, or —S(═O)2ORA1, wherein each instance of RA1is 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 RA1groups are joined to form an heterocyclic or heteroaryl ring; and RA2is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R11aand R1btogether with the carbon atom to which they are attached form a carbocyclyl, heterocyclyl, or —C(═O)— group; R3is alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; Q is halogen, cyano, nitro, heterocyclyl linked through a C atom, aryl, heteroaryl linked through a C atom, —O-alkenyl, —O-alkynyl, —SRA1, —N(RA1)2, —NHC(═O)RA1, —NHC(═O)ORA1, —S(═O)RA2, —SO2RA2, or —S(═O)2ORA1; R19is C(RC)2ORA1, wherein RCis hydrogen or alkyl; R5is absent or hydrogen; andrepresents a single or double bond, wherein when oneis a double bond, the otheris a single bond and R5is absent.

In an aspect, provided herein is a compound of the Formula (I):


or a pharmaceutically acceptable salt thereof, wherein: each of R2, R4, R6, R7, R11a, and R11bis independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, —N(RA1)2, —NHC(═O)RA1, —S(═O)RA2, —SO2RA2, or —S(═O)2ORA1, wherein each instance of RA1is 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 RA1groups are joined to form an heterocyclic or heteroaryl ring; and RA2is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R11aand R11btogether with the carbon atom to which they are attached form a carbocyclyl, heterocyclyl, or —C(═O)—; R3is hydrogen, alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; each of R17aand R17bis independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, —N(RA1)2, —NHC(═O)RA1, —S(═O)RA2, —SO2RA2, or —S(═O)2ORA1, wherein at least one of R17aand R17bis not hydrogen; R19is hydrogen or alkyl (e.g., unsubstituted alkyl or substituted alkyl (e.g., —C(RC)2ORA1, wherein RCis hydrogen or alkyl)); R5is absent or hydrogen; andrepresents a single or double bond, wherein when oneis a double bond, the otheris a single bond and R5is absent.

In some embodiments, R19is hydrogen or alkyl. In some embodiments, R19is unsubstituted alkyl. In some embodiments, R19is substituted alkyl. In some embodiments, R19is —CH2OH, —CH2OCH3, —CH2OCH2CH3, or —CH2OCH(CH3)2.

In some embodiments, R2is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, or —N(RA1)2. In some embodiments, R2is hydrogen, halogen, alkyl, or —ORA1. In some embodiments, R2is hydrogen.

In some embodiments, R3is alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, R3is alkyl (e.g., substituted or unsubstituted alkyl), alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, R3is methyl and ethyl (e.g., substituted or unsubstituted alkyl).

In some embodiments, R4is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, or —N(RA1)2. In some embodiments, R4is hydrogen, halogen, alkyl, or —ORA1. In some embodiments, R4is hydrogen.

In some embodiments,represents a single bond and R5is hydrogen. In some embodiments, R5is absent, andrepresents a single or double bond, wherein when oneis a double bond, the otheris a single bond.

In some embodiments, R6is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, or —N(RA1)2. In some embodiments, R6is hydrogen, halogen, alkyl, or —ORA1. In some embodiments, R6is hydrogen.

In some embodiments, R7is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, or —N(RA1)2. In some embodiments, R7is hydrogen, halogen, alkyl, or —ORA1. In some embodiments, R7is hydrogen.

In some embodiments, R11ais hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, —N(RA1)2, or R11aand R11btogether with the carbon atom to which they are attached form —C(═O)—. In some embodiments, R11ais hydrogen, halogen, alkyl, or —ORA1. In some embodiments, R11aand R11btogether with the carbon atom to which they are attached form —C(═O)—. In some embodiments, R11aand R11bare hydrogen.

In some embodiments, each of R2, R4, R6, R7, R11a, and R11bis independently hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, or —N(RA1)2. In some embodiments, each of R2, R4, R6, R7, R11a, and R11bis independently hydrogen, halogen, alkyl, or —ORA1. In some embodiments, R2, R4, R6, R7, R11a, and R11bare hydrogen.

In some embodiments, each of R17aand R17bis independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, —SRA1, —N(RA1)2, —NHC(═O)RA1—S(═O)RA2, —SO2RA2, or —S(═O)2ORA1, wherein at least one of R17aand R17bis not hydrogen. In some embodiments, each of R17aand R17bis independently hydrogen, halogen, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, —SRA1, —N(RA1)2, —NHC(═O)RA1—S(═O)RA2, —SO2RA2, or —S(═O)2ORA1, wherein at least one of R17aand R17bis not hydrogen.

In some embodiments, R17ais halogen, cyano, nitro, alkyl, carbocyclyl, heterocyclyl, —ORA1, —SRA1, —N(RA1)2, —NHC(═O)RA1, —S(═O)RA2, or —SO2RA2. In some embodiments, R17ais halogen, nitro, alkyl, carbocyclyl, heterocyclyl, —ORA1, —SRA1, —N(RA1)2, —NHC(═O)RA1, —S(═O)RA2, or —SO2RA2. In some embodiments, R17ais halogen, cyano, nitro, alkyl, —ORA1, —SRA1, or —N(RA1)2.

In some embodiments, the compound is:


or a pharmaceutically acceptable salt thereof.

In an aspect, provided herein is a compound of the Formula (II):


or a pharmaceutically acceptable salt thereof, wherein: each of R2, R4, R6, R7, R11a, and R11bis independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, —N(RA1)2, —NHC(═O)RA1, —NHC(═O)ORA1, —S(═O)RA2, —SO2RA2, or —S(═O)2ORA1, wherein each instance of RA1is 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 RA1groups are joined to form an heterocyclic or heteroaryl ring; and RA2is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R11aand R11btogether with the carbon atom to which they are attached form a carbocyclyl, heterocyclyl, or —C(═O)— group; R3is hydrogen, alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; A is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, —ORA1, —SRA1, or —N(RA1)2; R19is hydrogen or alkyl (e.g., unsubstituted alkyl (e.g., —CH3) or substituted alkyl (e.g., —C(RC)2ORA1, wherein RCis hydrogen or alkyl)); R5is absent or hydrogen; and
represents a single or double bond, wherein when oneis a double bond, the otheris a single bond and R5is absent.

In some embodiments, A is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, or —ORA1.

In some embodiments, R19is hydrogen. In some embodiments, R19is alkyl (e.g., substituted or unsubstituted alkyl). In some embodiments, R19is —CH3or —CH2CH3. In some embodiments, R19is —C(RC)2ORA1. In some embodiments, R19is —CH2OH, —CH2OCH3, —CH2OCH2CH3, or —CH2OCH(CH3)2.

In some embodiments, R2is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, or —N(RA1)2. In some embodiments, R2is hydrogen, halogen, alkyl, or —ORA1. In some embodiments, R2is hydrogen.

In some embodiments, R3is alkyl (e.g., substituted or unsubstituted alkyl). In some embodiments, R3is methyl and ethyl (e.g., substituted or unsubstituted methyl, substituted or unsubstituted ethyl).

In some embodiments, R4is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, or —N(RA1)2. In some embodiments, R4is hydrogen, halogen, alkyl, or —ORA1. In some embodiments, R4is hydrogen.

In some embodiments,represents a single bond and R5is hydrogen. In some embodiments, R5is absent, andrepresents a single or double bond, wherein when oneis a double bond, the otheris a single bond.

In some embodiments, R6is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, or —N(RA1)2. In some embodiments, R6is hydrogen, halogen, alkyl, or —ORA1. In some embodiments, R6is hydrogen.

In some embodiments, R7is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, or —N(RA1)2. In some embodiments, R7is hydrogen, halogen, alkyl, or —ORA1. In some embodiments, R7is hydrogen.

In some embodiments, R11ais hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, —N(RA1)2, or R11aand R11btogether with the carbon atom to which they are attached form —C(═O)—. In some embodiments, R11ais hydrogen, halogen, alkyl, or —ORA1. In some embodiments, R11aand R11btogether with the carbon atom to which they are attached form —C(═O)—. In some embodiments, R11aand R11bare hydrogen.

In some embodiments, each of R2, R4, R6, R7, R11a, and R11bis independently hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, or —N(RA1)2. In some embodiments, each of R2, R4, R6, R7, R11a, and R11bis hydrogen, halogen, alkyl, or —ORA1. In some embodiments, each of R2, R4, R6, R7, R11a, and R11bis hydrogen.

In some embodiments, the compound of Formula (II) is a compound of the Formula (II-a) or (II-b):



In some embodiments, the compound of Formula (I) is a compound of the Formula (II-c):


wherein:
each of R21aand R21bis independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, —N(RA1)2, —NHC(═O)RA1, —NHC(═O)ORA1, —S(═O)RA2, —SO2RA2, or —S(═O)2ORA1; or R21aand R21btogether 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, —ORA1, —SRA1, or —N(RA1)2; and n is an integer selected from 1, 2, and 3.

In some embodiments, the compound of Formula (II) is a compound of the Formula (II-d):


In an aspect, provided herein is a compound of the Formula (III-a):


wherein:
or a pharmaceutically acceptable salt thereof, wherein: each of R2, R4, R6, R7, R11a, and R11bis independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, —N(RA1)2, —NHC(═O)RA1, —NHC(═O)ORA1, —S(═O)RA2, —SO2RA2, or —S(═O)2ORA1, wherein each instance of RA1is 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 RA1groups are joined to form an heterocyclic or heteroaryl ring; and RA2is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R11aand R11btogether 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, —ORA1, —SRA1, or —N(RA1)2; R19is unsubstituted alkyl; R5is absent or hydrogen; andrepresents a single or double bond, wherein when oneis a double bond, the otheris a single bond and R5is absent.

In an aspect, provided herein is a compound of the Formula (III-b):


or a pharmaceutically acceptable salt thereof, wherein: each of R2, R4, R6, R7, R11a, and R11bis independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —ORA1, —SRA1, —N(RA1)2, —NHC(═O)RA1, —NHC(═O)ORA1, —S(═O)RA2, —SO2RA2, or —S(═O)2ORA1, wherein each instance of RA1is 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 RA1groups are joined to form an heterocyclic or heteroaryl ring; and RA2is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R11aand R11btogether with the carbon atom to which they are attached form a carbocyclyl, heterocyclyl, or —C(═O)— group; R3is alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; Q is halogen, cyano, nitro, heterocyclyl linked through a C atom, aryl, heteroaryl linked through a C atom, —O-alkenyl, —O-alkynyl, —SRA1, —N(RA1)2, —NHC(═O)RA1, —NHC(═O)ORA1, —S(═O)RA2, —SO2RA2, or —S(═O)2ORA1; R19is —C(RC)2ORA1, wherein RCis hydrogen or alkyl; R5is absent or hydrogen; andrepresents a single or double bond, wherein when oneis a double bond, the otheris a single bond and R5is absent.

In an aspect, provided herein is a compound of Formula (1-A):


or a pharmaceutically acceptable salt thereof, wherein: R3is alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; each of RXand RYis independently hydrogen, aryl, or alkyl, or
RXand RYare joined together to form a 3-10 membered heterocyclic ring; R19is hydrogen or alkyl (e.g., unsubstituted alkyl or substituted alkyl (e.g., —C(RC)2ORA1, wherein RCis hydrogen or alkyl)); R5is absent or hydrogen;represents a single or double bond, wherein when oneis a double bond, the otheris a single bond and R5is absent; and a is 0 or 1; provided that RXand RYare joined together to form a 3-8 membered heterocyclic ring only when a is 0.

In some embodiments, RXand RYare not both hydrogen. In some embodiments, R3is alkyl. In some embodiments, R19is hydrogen.

In some embodiments, the compound is a compound of Formula (1-A-1)


wherein each instance of RY4is independently alkyl, cyano, or halo; and e is 0, 1, 2, 3, 4, or 5.

In some embodiments, each instance of RY4is independently hydrogen, —CH3, —CN, or —F. In some embodiments, e is 3. In some embodiments, RXis hydrogen. In some embodiments, each instance of RY4is independently hydrogen, —CH3, —CN, or —F, RXis hydrogen, and e is 3. In some embodiments, each instance of RY4is independently hydrogen, —CH3, —CN, or —F, RXis hydrogen, and e is 2. In some embodiments, e is 1. In some embodiments, RY4is —F. In some embodiments, RY4is —F and e is 1.

In some embodiments, the compound is a compound of Formula (1-A-2)



In some embodiments, each instance of RY4is independently hydrogen, —CH3, —CN, or —F. In some embodiments, e is 3. In some embodiments, RXis hydrogen. In some embodiments, each instance of RY4is independently hydrogen, —CH3, —CN, or —F, RXis hydrogen, and e is 3. In some embodiments, each instance of RY4is independently hydrogen, —CH3, —CN, or —F, RXis hydrogen, and e is 2. In some embodiments, e is 1. In some embodiments, RY4is —F.

In some embodiments, the compound is a compound of Formula (1-A-3)


wherein each of RY1and RY2is independently alkyl, cycloalkyl, heterocycyl, aryl, or heteroaryl; and b=0, 1, 2, 3.

In some embodiments, RY1and RY2are not both —CH(CH3)2.

In some embodiments, the compound is a compound of Formula (1-A-4)



In some embodiments, RY1is hydrogen, —CH3, or —CH2CH3, —CH(CH3)2, or cycloalkyl. In some embodiments, R3is —CH3, —CF3, —CH2OCH3, —CH2OCH2CH3. In some embodiments, RY2is heteocyclyl, aryl, or heteroaryl. In some embodiments, RY2is aryl substituted with 0-5 occurrences of —CH3, —CN, —F, —CF3, or combinations thereof or heteroaryl substituted with 0-5 occurrences of —CH3, —CN, —F, —CF3.

In some embodiments, RY2is aryl substituted with 0-5 occurrences of —CH3, —CN, —F, —CF3, or RXis hydrogen, —CH3, or —CH2CH3. In some embodiments, RY2is aryl substituted with 0-5 occurrences of —CH3, —CN, —F, —CF3.

In some embodiments, the compound is a compound of Formula (1-A-5)


wherein each occurrence of RY3is aryl or heteroaryl, or two RY3groups are joined together to form a 6-10 membered ring; c is 0, 1, 2, or 3; and d is 0, 1, 2, or 3.

In some embodiments, the compound is a compound of Formula (1-A-6)



In some embodiments, if d is 2, then two RY3groups are joined together to form aryl. In some embodiments, RY2is aryl substituted with 0-5 occurrences of —CH3, —CN, —F, —CF3. In some embodiments, the compound is a compound of Formula (1-A-7) or Formula (1-A-8)



In some embodiments, RY2is aryl substituted with 0-5 occurrences of —CH3, —CN, —F, —CF3, or R3is —CH3, —CF3, —CH2OCH3, —CH2OCH2CH3.

In an aspect, provided herein is a compound of Formula (2-A),


or a pharmaceutically acceptable salt thereof, wherein R3is —CH3, —CF3, —CH2OCH3, —CH2OCH2CH3; R19is hydrogen, —CH3, or —CH2ORA1, wherein RA1is optionally substituted alkyl; R3is —CH3, —CF3, —CH2OCH3, —CH2OCH2CH3; R17ais —NRA2RA3, —N(R1)C(O)RA2, —N(R1)SO2RA2, —ORA3, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of RA2and RA3is independently hydrogen, carbocyclyl, heterocyclyl, aryl, heteroaryl, or —ORA4, wherein RA4is hydrogen or alkyl; or R17Ais


wherein A is oxazolyl or thiazolyl; R17ais hydrogen, hydroxyl, alkyl, or alkoxy; andrepresents a single or double bond, wherein when oneis a double bond, the otheris a single bond and R5is absent; provided that: when R17ais oxazolyl or


then R17bis not hydrogen, or when R17ais heterocyclyl, then R19is hydrogen, or when R17ais —ORA4, then R19is hydrogen.

In some embodiments, R17ais —NRA2RA3, —N(R1)C(O)RA2, —N(R1)SO2RA2. In some embodiments, R17ais aryl, heteroaryl, cycloalkyl, or heterocyclyl. In some embodiments, R19is hydrogen. In some embodiments, R17ais heteroaryl. In some embodiments, R17ais heteroaryl and R19is hydrogen. In some embodiments, R17ais pyridyl and R19is hydrogen.

In an aspect, provided herein is a compound of Formula (3-A)


or a pharmaceutically acceptable salt thereof, wherein R19is hydrogen or alkyl; R17ais nitro or alkoxy (e.g., —OCH3); each of R2, R4, R11a, or R11bis independently hydrogen, alkyl, or alkoxy, or R11aand R11bare joined together to form oxo;represents a single or double bond, wherein when oneis a double bond, the otheris a single bond and R5is absent; and R5is absent or hydrogen as determined by valency; provided that, when R2, R11a, and R11bare hydrogen, then R4is alkyl, or when R4, R11a, and R11bare hydrogen, then R2is alkyl, or when R4is hydrogen, then R2is —OH or alkoxy, R11ais hydrogen, and R11bis —OH or alkoxy, or R2is —OH or alkoxy and R11aand R11bare joined together to form oxo.

In some embodiments, R4is hydrogen, R2is —OH or alkoxy, R11ais hydrogen, and R11bis —OH or alkoxy. In some embodiments, R4is hydrogen, R2is —OH or alkoxy, and R11aand R11bare joined together to form oxo. In some embodiments, R17ais nitro. In some embodiments, R17ais alkoxy. In some embodiments, R17ais methoxy and R2is methyl.

In an aspect, also provided herein are compounds described in Table 1 or pharmaceutically acceptable salts thereof.

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

In an 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 the Formula (I), Formula (II), Formula (III), or Formula (IV), Formula (1-A), Formula (2-A), or Formula (3-A)), or a pharmaceutically acceptable salt thereof.

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

In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

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

In an aspect, provided herein is a method for treating seizure in a subject, comprising administering to the subject an effective amount of a compound described herein (e.g., a compound of the Formula (I), Formula (II), Formula (III), or Formula (IV), Formula (1-A), Formula (2-A), or Formula (3-A)).

In an aspect, provided herein is a method for 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 the Formula (I), Formula (II), Formula (III), or Formula (IV), Formula (1-A), Formula (2-A), or Formula (3-A)).

In an aspect, provided herein is a method for treating a neuroendocrine disorder or dysfunction in a subject, comprising administering to the subject an effective amount of a compound described herein (e.g., a compound of the Formula (I), Formula (II), Formula (III), or Formula (IV), Formula (1-A), Formula (2-A), or Formula (3-A)).

In an aspect, provided herein is a method for treating a neurodegenerative disease or disorder in a subject, comprising administering to the subject an effective amount of a compound described herein (e.g., a compound of the Formula (I), Formula (II), Formula (III), or Formula (IV), Formula (1-A), Formula (2-A), or Formula (3-A)).

In an aspect, provided herein is a method for treating a movement disorder or tremor in a subject, comprising administering to the subject an effective amount of a compound described herein (e.g., a compound of the Formula (I), Formula (II), Formula (III), or Formula (IV), Formula (1-A), Formula (2-A), or Formula (3-A)).

In an aspect, provided herein is a method for treating a mood disorder or anxiety disorder in a subject, comprising administering to the subject an effective amount of a compound described herein (e.g., a compound of the Formula (I), Formula (II), Formula (III), or Formula (IV), Formula (1-A), Formula (2-A), or Formula (3-A)).

In an aspect, provided herein is a method for treating disorders related to GABA function in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound, a pharmaceutically acceptable salt thereof, or pharmaceutical composition of a compound described herein (e.g., a compound of the Formula (I), Formula (II), Formula (III), or Formula (IV), Formula (1-A), Formula (2-A), or Formula (3-A)).

In an aspect, provided herein is a kit comprising a solid composition comprising a compound described herein (e.g., a compound of the Formula (I), Formula (II), Formula (III), or Formula (IV), Formula (1-A), Formula (2-A), or Formula (3-A)) and a sterile diluent.

Thus, in another aspect, provided are methods of treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound as described herein (e.g., a compound of the 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 a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, and tinnitus. In certain embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered chronically. In certain embodiments, the compound is administered continuously, e.g., by continuous intravenous infusion.

In some embodiments, the subject is a subject with Rett syndrome, Fragile X syndrome, or Angelman syndrome.

Definitions

Chemical Definitions

Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics,75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell,Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March,March's Advanced Organic Chemistry,5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock,Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis,3rdEdition, Cambridge University Press, Cambridge, 1987.

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 syntheses. See, for example, Jacques et al.,Enantiomers, Racemates and Resolutions(Wiley Interscience, New York, 1981); Wilen et al.,Tetrahedron33:2725 (1977); Eliel,Stereochemistry of Carbon Compounds(McGraw-Hill, N Y, 1962); and Wilen,Tables of Resolving Agents and Optical Resolutionsp. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972). The invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

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

In some embodiments, an asymmetric center of known absolute configuration can be introduced into a compound with a chiral reactant, e.g., a chiral amine. In some embodiments, an asymmetric center of known absolute configuration can be introduced into a compound with a reaction methodology, e.g., by a reductive amination.

As used herein a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form. The term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound.

In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R-compound in such compositions can, for example, comprise, at least about 95% by weight R-compound and at most about 5% by weight S-compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure S-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S-compound in such compositions can, for example, comprise, at least about 95% by weight S-compound and at most about 5% by weight R-compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.

The articles “a” and “an” may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example “an analogue” means one analogue or more than one analogue.

When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example “C1-6alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6alkyl.

The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention.

“Alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1-20alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-12alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6alkyl”, also referred to herein as “lower alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6alkyl”). Examples of C1-6alkyl 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). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C5) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted C1-10alkyl (e.g., —CH3). In certain embodiments, the alkyl group is substituted C1-10alkyl. Common alkyl abbreviations include Me (—CH3), Et (—CH2CH3), iPr (—CH(CH3)2), nPr (—CH2CH2CH3), n-Bu (—CH2CH2CH2CH3), or i-Bu (—CH2CH(CH3)2).

“Alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds (“C2-20alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-10alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-3alkenyl groups include the aforementioned C2-4alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is unsubstituted C2-10alkenyl. In certain embodiments, the alkenyl group is substituted C2-10alkenyl.

“Alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more double bonds (“C2-20alkynyl”). In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-10alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6alkenyl groups include the aforementioned C2-4alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkynyl group is unsubstituted C2-10alkynyl. In certain embodiments, the alkynyl group is substituted C2-10alkynyl.

“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 n electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate 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 instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is unsubstituted C6-14aryl. In certain embodiments, the aryl group is substituted C6-14aryl.

In certain embodiments, an aryl group substituted with one or more of groups selected from halo, C1-C8alkyl, C1-C8haloalkyl, cyano, hydroxy, C1-C8alkoxy, and amino.

Examples of representative substituted aryls include the following


wherein one of R56and R57may be hydrogen and at least one of R56and R57is each independently selected from C1-C8alkyl, C1-C8haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C1-C8alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR58COR59, NR58SOR59NR58SO2R59, COOalkyl, COOaryl, CONR58R59, CONR58OR59, NR58R59, SO2NR58R59, S-alkyl, SOalkyl, SO2alkyl, Saryl, SOaryl, SO2aryl; or R56and R57may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O, or S. R60and R61are independently hydrogen, C1-C8alkyl, C1-C4haloalkyl, C3-C10cycloalkyl, 4-10 membered heterocyclyl, C6-C10aryl, substituted C6-C10aryl, 5-10 membered heteroaryl, or substituted 5-10 membered heteroaryl.

Other representative aryl groups having a fused heterocyclyl group include the following:


wherein each W is selected from C(R66)2, NR66, O, and S; and each Y is selected from carbonyl, NR66, O and S; and R66is independently hydrogen, C1-C8alkyl, C3-C10cycloalkyl, 4-10 membered heterocyclyl, C6-C10aryl, and 5-10 membered heteroaryl.

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

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

“Hydroxy” or “hydroxyl,” independently or as part of another substituent, mean, unless otherwise stated, a —OH group.

Hydroxyalkyl” or “hydroxylalkyl” can include alkyl structures that are substituted with one or more hydroxyl groups.

“Heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or □ □ □ □ electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

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

Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

Examples of representative heteroaryls include the following formulae:


wherein each Y is selected from carbonyl, N, NR65, O, and S; and R65is independently hydrogen, C1-C8alkyl, C3-C10cycloalkyl, 4-10 membered heterocyclyl, C6-C10aryl, and 5-10 membered heteroaryl.

“Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C3-10carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10carbocyclyl”). Exemplary C3-6carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8carbocyclyl groups include, without limitation, the aforementioned C3-6carbocyclyl 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. Exemplary C3-10carbocyclyl groups include, without limitation, the aforementioned C3-8carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C3-10carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-10carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C3-10cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10cycloalkyl”). Examples of C5-6cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6cycloalkyl groups include the aforementioned C5-6cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8cycloalkyl groups include the aforementioned C3-6cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C3-10cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C3-10cycloalkyl.

“Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3-10 membered heterocyclyl.

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

Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

Particular examples of heterocyclyl groups are shown in the following illustrative examples:


wherein each W is selected from CR67, C(R67)2, NR67, O, and S; and each Y is selected from NR67, O, and S; and R67is independently hydrogen, C1-C8alkyl, C3-C10cycloalkyl, 4-10 membered heterocyclyl, C6-C10aryl, and 5-10-membered heteroaryl. These heterocyclyl rings may be optionally substituted with one or more groups selected from the group consisting of 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, —S-alkyl, —S-aryl, —S(O)-alkyl, —S(O)-aryl, —S(O)2-alkyl, and —S(O)2-aryl. Substituting groups include carbonyl or thiocarbonyl which provide, for example, lactam and urea derivatives.

“Acyl” refers to a radical —C(O)R20, where R20is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein. “Alkanoyl” is an acyl group wherein R20is a group other than hydrogen. Representative acyl groups include, but are not limited to, formyl (—CHO), acetyl (—C(═O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (—C(═O)Ph), benzylcarbonyl (—C(═O)CH2Ph), —C(O)—C1-C8alkyl, —C(O)—(CH2)t(C6-C10aryl), —C(O)—(CH2)t(5-10 membered heteroaryl), —C(O)—(CH2)t(C3-C10cycloalkyl), and —C(O)—(CH2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4. In certain embodiments, R21is C1-C8alkyl, substituted with halo or hydroxy; or C3-C10cycloalkyl, 4-10 membered heterocyclyl, C6-C10aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4alkyl, halo, unsubstituted C1-C4alkoxy, unsubstituted C1-C4haloalkyl, unsubstituted C1-C4hydroxyalkyl, or unsubstituted C1-C4haloalkoxy or hydroxy.

“Acylamino” refers to a radical —NR22C(O)R23, where each instance of R22and R23is 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 R22is an amino protecting group. Exemplary “acylamino” groups include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino and benzylcarbonylamino. Particular exemplary “acylamino” groups are —NR24C(O)C1-C8alkyl, —NR24C(O)—(CH2)t(C6-C10aryl), —NR24C(O)—(CH2)t(5-10 membered heteroaryl), —NR24C(O)—(CH2)t(C3-C10cycloalkyl), and —NR24C(O)—(CH2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, and each R24independently represents hydrogen or C1-C8alkyl. In certain embodiments, R25is H, C1-C8alkyl, substituted with halo or hydroxy; C3-C10cycloalkyl, 4-10 membered heterocyclyl, C6-C10aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4alkyl, halo, unsubstituted C1-C4alkoxy, unsubstituted C1-C4haloalkyl, unsubstituted C1-C4hydroxyalkyl, or unsubstituted C1-C4haloalkoxy or hydroxy; and R26is H, C1-C8alkyl, substituted with halo or hydroxy; C3-10cycloalkyl, 4-10-membered heterocyclyl, C6-C10aryl, arylalkyl, 5-10-membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4alkyl, halo, unsubstituted C1-C4alkoxy, unsubstituted C1-C4haloalkyl, unsubstituted C1-C4hydroxyalkyl, or unsubstituted C1-C4haloalkoxy or hydroxy; provided at least one of R25and R26is other than H.

“Acyloxy” refers to a radical —OC(O)R27, where R27is 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, R28is C1-C8alkyl, substituted with halo or hydroxy; C3-C10cycloalkyl, 4-10-membered heterocyclyl, C6-C10aryl, arylalkyl, 5-10-membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4alkyl, halo, unsubstituted C1-C4alkoxy, unsubstituted C1-C4haloalkyl, unsubstituted C1-C4hydroxyalkyl, or unsubstituted C1-C4haloalkoxy or hydroxy.

“Alkoxy” refers to the group —OR29where R29is 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., with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.

In certain embodiments, R29is a group that has 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino, C6-C10aryl, aryloxy, carboxyl, cyano, C3-C10cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxy, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)2— and aryl-S(O)2—. Exemplary “substituted alkoxy” groups include, but are not limited to, —O—(CH2)t(C6-C10aryl), —O—(CH2)t(5-10 membered heteroaryl), —O—(CH2)t(C3-C10cycloalkyl), and —O—(CH2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves be substituted by unsubstituted C1-C4alkyl, halo, unsubstituted C1-C4alkoxy, unsubstituted C1-C4haloalkyl, unsubstituted C1-C4hydroxyalkyl, or unsubstituted C1-C4haloalkoxy or hydroxy. Particular exemplary ‘substituted alkoxy’ groups are —OCF3, —OCH2CF3, —OCH2Ph, —OCH2-cyclopropyl, —OCH2CH2OH, and —OCH2CH2NMe2.

“Amino” refers to the radical —NH2.

“Oxo” refers to ═O.

“Substituted amino” refers to an amino group of the formula —N(R38)2wherein R38is 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 at least one of R38is not a hydrogen. In certain embodiments,

each R38is independently selected from hydrogen, C1-C8alkyl, C3-8alkenyl, C3-C8alkynyl, C6-C10aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, or C3-C10cycloalkyl; or C1-C8alkyl, substituted with halo or hydroxy; C3-C8alkenyl, substituted with halo or hydroxy; C3-C8alkynyl, substituted with halo or hydroxy, or —(CH2)t(C6-C10aryl), —(CH2)t(5-10 membered heteroaryl), —(CH2)t(C3-C10cycloalkyl), or —(CH2)t(4-10 membered heterocyclyl), wherein t is an integer between 0 and 8, each of which is substituted by unsubstituted C1-C4alkyl, halo, unsubstituted C1-C4alkoxy, unsubstituted C1-C4haloalkyl, unsubstituted C1-C4hydroxyalkyl, or unsubstituted C1-C4haloalkoxy or hydroxy; or both R38groups are joined to form an alkylene group.

Exemplary “substituted amino” groups include, but are not limited to, —NR39—C1-C8alkyl, —NR39—(CH2)t(C6-C10aryl), —NR39—(CH2)t(5-10 membered heteroaryl), —NR39—(CH2)t(C3-C10cycloalkyl), and —NR39—(CH2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, for instance 1 or 2, each R39independently represents hydrogen or C1-C8alkyl; and any alkyl groups present, may themselves be substituted by halo, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryl, cycloalkyl, or heterocyclyl groups present, may themselves be substituted by unsubstituted C1-C4alkyl, halo, unsubstituted C1-C4alkoxy, unsubstituted C1-C4haloalkyl, unsubstituted C1-C4hydroxyalkyl, or unsubstituted C1-C4haloalkoxy or hydroxy. For the avoidance of doubt the term ‘substituted amino’ includes the groups alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino as defined below. Substituted amino encompasses both monosubstituted amino and disubstituted amino groups.

“Azido” refers to the radical —N3.

“Carbamoyl” or “amido” refers to the radical —C(O)NH2.

“Substituted carbamoyl” or “substituted amido” refers to the radical —C(O)N(R62)2wherein each R62is 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 at least one of R62is not a hydrogen. In certain embodiments, R62is selected from H, C1-C8alkyl, C3-C10cycloalkyl, 4-10 membered heterocyclyl, C6-C10aryl, and 5-10 membered heteroaryl; or C1-C8alkyl substituted with halo or hydroxy; or C3-C10cycloalkyl, 4-10 membered heterocyclyl, C6-C10aryl, or 5-10 membered heteroaryl, each of which is substituted by unsubstituted C1-C4alkyl, halo, unsubstituted C1-C4alkoxy, unsubstituted C1-C4haloalkyl, unsubstituted C1-C4hydroxyalkyl, or unsubstituted C1-C4haloalkoxy or hydroxy; provided that at least one R62is other than H.

“Carboxy” refers to the radical —C(O)OH.

“Cyano” refers to the radical —CN.

“Nitro” refers to the radical —NO2.

“Ethenyl” refers to substituted or unsubstituted —(C═C)—. “Ethylene” refers to substituted or unsubstituted —(C—C)—. “Ethynyl” refers to —(C≡C)—.

“Nitrogen-containing heterocyclyl” group means a 4- to 7-membered non-aromatic cyclic group containing at least one nitrogen atom, for example, but without limitation, 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-alkyl piperazines such as N-methyl piperazine. Particular examples include azetidine, piperidone and piperazone.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, 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 group). 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 a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.

Exemplary carbon atom substituents include, but are not limited to, halogen, —CN, —NO2, —N3, —SO2H, —SO3H, —OH, —ORaa, —ON(Rbb)2, —N(Rbb)2, —N(Rbb)3+X−, —N(ORcc)Rbb, —SH, —SRaa, —SSRcc, —C(═O)Raa, —CO2H, —CHO, —C(ORcc)2, —CO2Raa, —OC(═O)Raa, —OCO2Raa, —C(═O)N(Rbb)2, —OC(═O)N(Rbb)2, —NRbbC(═O)Raa, —NRbbCO2Raa, —NRbbC(═O)N(Rbb)2, —C(═NRbb)Raa, —C(═NRbb)ORaa, —OC(═NRbb)Raa, —OC(═NRbb)ORaa, —C(═NRbb)N(Rbb)2, —OC(═NRbb)N(Rbb)2, —NRbbC(═NRbb)N(Rbb)2, C(═O)NRbbSO2Raa, —NRbbSO2Raa, —SO2N(Rbb)2, —SO2Raa, —SO2ORaa, —OSO2Raa, —S(═O)Raa, —OS(═O)Raa, —Si(Raa)3, —OSi(Raa)3—C(═S)N(Rbb)2, —C(═O)SRaa, —C(═S)SRaa, —SC(═S)SRaa, —SC(═O)SRaa, —OC(═O)SRaa, —SC(═O)ORaa, —SC(═O)Raa, —P(═O)2Raa, —OP(═O)2Raa, —P(═O)(Raa)2, —OP(═O)(Raa)2, —OP(═O)(ORcc)2, —P(═O)2N(Rbb)2, —OP(═O)2N(Rbb)2, —P(═O)(NRbb)2, —OP(═O)(NRbb)2, —NRbbP(═O)(ORcc)2, —NRbbP(═O)(NRbb)2, —P(Rcc)2, —P(Rcc)3, —OP(Rcc)2, —OP(Rcc)3, —B(Raa)2, —B(ORcc)2, —BRaa(ORcc), C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups;

each instance of Raais, independently, selected from C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups;

each instance of Rbbis, independently, selected from hydrogen, —OH, —ORaa, —N(RC)2, —CN, —C(═O)Raa, —C(═O)N(Rcc)2, —CO2Raa, —SO2Raa, —C(═NRcc)ORaa, —C(═NRcc)N(Rcc)2, —SO2N(Rcc)2, —SO2Rcc, —SO2ORcc, —SORaa, —C(═S)N(Rcc)2, —C(═O)SRcc, —C(═S)SRcc, —P(═O)2Raa, —P(═O)(Raa)2, —P(═O)2N(Rcc)2, —P(═O)(NRcc)2, C1-C10alkyl, C1-C10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups;

each instance of Rccis, independently, selected from hydrogen, C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups;

each instance of Rddis, independently, selected from halogen, —CN, —NO2, —N3, —SO2H, —SO3H, —OH, —ORee, —ON(Rff)2, —N(Rff)2, —N(Rff)3+X−, —N(ORee)Rff, —SH, —SRee, —SSRee, —C(═O)Ree, —CO2H, —CO2Ree, —OC(═O)Ree, OCO2Ree, —C(═O)N(Rff)2, —OC(═O)N(Rff)2, —NRffC(═O)Ree, —NRffCO2Ree, —NRffC(═O)N(Rff)2, —C(═NRff)ORee, —OC(═NRff)Ree, —OC(═NRff)ORee, —C(═NRff)N(Rff)2, —OC(═NRff)N(Rff)2, —NRffC(═NRff)N(Rff)2, —NRffSO2Ree, —SO2N(Rff)2, —SO2Ree, —SO2ORee, —OSO2Ree, —S(═O)Ree, —Si(Ree)3, —OSi(Ree)3, —C(═S)N(Rff)2, —C(═O)SRee, C(═S)SRee, —SC(═S)SRee, —P(═O)2Ree, —P(═O)(Ree)2, —OP(═O)(Ree)2, —OP(═O)(ORee)2, C1-6alkyl, C1-6perhaloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups;

each instance of Reeis, independently, selected from C1-6alkyl, C1-6perhaloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups;

each instance of Rffis, independently, selected from hydrogen, C1-6alkyl, C1-6perhaloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; and

each instance of Rggis, independently, halogen, —CN, —NO2, —N3, —SO2H, —SO3H, —OH, —OC1-6alkyl, —ON(C1-6alkyl)2, —N(C1-6alkyl)2, —N(C1-6alkyl)3+X−, —NH(C1alkyl)2+X−, —NH2(C1-6alkyl)+X, —NH3+X−, —N(OC1-6alkyl)(C1-6alkyl), —N(OH)(C1-6alkyl), —NH(OH), —SH, —SC1-6alkyl, —SS(C1-6alkyl), —C(═O)(C1-6alkyl), —CO2H, —CO2(C1-6alkyl), —OC(═O)(C1-6alkyl), —OCO2(C1-6alkyl), —C(═O)NH2, —C(═O)N(C1-6alkyl)2, —OC(═O)NH(C1-6alkyl), —NHC(═O)(C1-6alkyl), —N(C1-6alkyl)C(═O)(C1-6alkyl), —NHCO2(C1-6alkyl), —NHC(═O)N(C1-6alkyl)2, —NHC(═O)NH(C1-6alkyl), —NHC(═O)NH2, —C(═NH)O(C1-6alkyl), —OC(═NH)(C1-6alkyl), —OC(═NH)OC1-6alkyl, —C(═NH)N(C1-6alkyl)2, —C(═NH)NH(C1-6alkyl), —C(═NH)NH2, —OC(═NH)N(C1-6alkyl)2, —OC(NH)NH(C1-6alkyl), —OC(NH)NH2, —NHC(NH)N(C1-6alkyl)2, —NHC(═NH)NH2, —NHSO2(C1-6alkyl), —SO2N(C1-6alkyl)2, —SO2NH(C1-6alkyl), —SO2NH2, —SO2C1-6alkyl, —SO2OC1-6alkyl, —OSO2C1-6alkyl, —SOC1-6alkyl, —Si(C1-6alkyl)3, —OSi(C1-6alkyl)3-C(═S)N(C1-6alkyl)2, C(═S)NH(C1-6alkyl), C(═S)NH2, —C(═O)S(C1-6alkyl), —C(═S)SC1-6alkyl, —SC(═S)SC1-6alkyl, —P(═O)2(C1-6alkyl), —P(═O)(C1-6alkyl)2, —OP(═O)(C1-6alkyl)2, —OP(═O)(OC1-6alkyl)2, C1-6alkyl, C1-6perhaloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; wherein X is a counterion.

A “counterion” or “anionic counterion” is a negatively charged group associated with a cationic quaternary amino group in order to maintain electronic neutrality. Exemplary counterions include halide ions (e.g., F−, Cl−, Br−, I−), NO3−, ClO4−, OH−, H2PO4−, HSO4−, sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonic acid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, and the like).

Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substitutents include, but are not limited to, hydrogen, —OH, —ORaa, —N(Rcc)2, —CN, —C(═O)Raa, —C(═O)N(Rcc)2, —CO2Raa, —SO2Raa, —C(═NRbb)Raa, —C(═NR)ORaa, —C(═NRcc)N(Rcc)2, —SO2N(Rcc)2, —SO2Rcc, —SO2ORcc, —SORaa, —C(═S)N(Rcc)2, —C(═O)SRcc, —C(═S)SRcc, —P(═O)2Raa, —P(═O)(Raa)2, —P(═O)2N(Rcc)2, —P(═O)(NRcc)2, C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14-membered heteroaryl, or two Rccgroups attached to a nitrogen atom are joined to form a 3-14-membered heterocyclyl or 5-14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined above.

In certain embodiments, the substituent present on a nitrogen atom is an amino protecting group (also referred to herein as a nitrogen protecting group). Amino protecting groups include, but are not limited to, —OH, —ORaa, —N(Rcc)2, —C(═O)Raa, —C(═O)ORaa, —C(═O)N(Rcc)2, —S(═O)2Raa, —C(═NRcc)Raa, —C(═NRcc)ORaa, —C(═NRcc)N(Rcc)2, —SO2N(Rcc)2, —SO2Rcc, —SO2ORcc, —SORaa, —C(═S)N(Rcc)2, —C(═O)SRcc, —C(═S)SRcc, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3_10carbocyclyl, 3-14-membered heterocyclyl, C6-14aryl, and 5-14-membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined herein. Amino protecting groups are well known in the art and include those described in detail inProtecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

Exemplary amino protecting groups include, but are not limited to amide groups (e.g., —C(═O)Raa), which include, but are not limited to, formamide and acetamide; carbamate groups (e.g., —C(═O)ORaa), which include, but are not limited to, 9-fluorenylmethyl carbamate (Fmoc), t-butyl carbamate (BOC), and benzyl carbamate (Cbz); sulfonamide groups (e.g., —S(═O)2Raa), which include, but are not limited to, p-toluenesulfonamide (Ts), methanesulfonamide (Ms), and N-[2-(trimethylsilyl)ethoxy]methylamine (SEM).

In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups include, but are not limited to, —Raa, —N(Rbb)2, —C(═O)SRaa, —C(═O)Raa, —CO2Raa, —C(═O)N(Rbb)2, —C(═NRbb)Raa, —C(═NRbb)ORaa, —C(═NRbb)N(Rbb)2, —S(═O)Raa, —SO2Raa, —Si(Raa)3—P(Rcc)2, —P(Rcc)3, —P(═O)2Raa, —P(═O)(Raa)2, —P(═O)(ORcc)2, —P(═O)2N(Rbb)2, and —P(═O)(NRbb)2, wherein Raa, Rbb, and Rccare as defined herein. Oxygen protecting groups are well known in the art and include those described in detail inProtecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

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).

In certain embodiments, the substituent present on an sulfur atom is an sulfur protecting group (also referred to as a thiol protecting group). Sulfur protecting groups include, but are not limited to, —Raa, —N(Rbb)2, —C(═O)SRaa, —C(═O)Raa, —CO2Raa, —C(═O)N(Rbb)2, —C(═NRbb)Raa, —C(═NRbb)ORaa, —C(═NRbb)N(Rbb)2, —S(═O)Raa, —SO2Raa, —Si(Raa)3—P(Rcc)2, —P(Rcc)3, —P(═O)2Raa, —P(═O)(Raa)2, —P(═O)(ORcc)2, —P(═O)2N(Rbb)2, and —P(═O)(NRbb)2, wherein Raa, Rbb, and Rccare as defined herein. Sulfur protecting groups are well known in the art and include those described in detail inProtecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents.

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) may be, for example, an agonist, partial agonist, antagonist, or partial antagonist of the GABA receptor.

“Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, 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 counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. See, e.g., Berge, et al.,J. Pharm. Sci. (1977) 66(1): 1-79.

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

“Stereoisomers”: It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (−)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

“Tautomers” refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of π electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro-forms of phenylnitromethane, that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, 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.

Disease, disorder, and condition are used interchangeably herein.

As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (“therapeutic treatment”), and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition (“prophylactic treatment”).

In general, the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response, e.g., to treat a CNS-related disorder, is sufficient to induce anesthesia or sedation. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject. An effective amount encompasses therapeutic and prophylactic treatment.

As used herein, and 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 therapeutic agent, alone or in combination with other therapies, which 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 therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

As used herein, and unless otherwise specified, a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which 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 enhances the prophylactic efficacy of another prophylactic agent.

