Aza-, oxa and thia-pregnan-20-one-3α-ol compounds for use in treating CNS disorders

Abstract

To provide novel and improved compounds that act as modulators of brain excitability and as agents for the prevention and treatment of CNS-related disorders.SOLUTION: Aza-, oxa-, and thia-pregnan-20-one-3α-ol compounds are provided.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims priority and benefit of U.S. Provisional Patent Application No. 62 / 617,134, filed on January 12, 2018; U.S. Provisional Patent Application No. 62 / 616,768, filed on January 12, 2018; and U.S. Provisional Patent Application No. 62 / 728,514, filed on September 7, 2018. The entireties of each of these U.S. Provisional Patent Applications are incorporated herein by reference.

Background Art

[0002] Background of the Invention Brain excitability is defined as the continuous arousal level of an animal ranging from coma to seizure and is controlled by various neurotransmitters. Generally, neurotransmitters are involved in controlling the conductance of ions across the neuron membrane. At rest, the neuron membrane has a potential (or membrane voltage) of approximately -70 mV, and the cell interior is negative relative to the cell exterior. The potential (voltage) is the result of the balance of ions (K + , Na + , Cl - , organic anions) across the neuron semi - permeable membrane. Neurotransmitters are stored in presynaptic vesicles and are released under the influence of neuronal action potentials. When released into the synaptic cleft, a potential change from -70 mV to -50 mV occurs. This effect is mediated by postsynaptic nicotinic receptors stimulated by acetylcholine, which increases the membrane permeability to Na + ions. The decreased membrane potential stimulates the excitability of the neuron in the form of a postsynaptic action potential.

[0003] In the case of the GABA receptor complex (GRC), the effect on brain excitability is mediated by the neurotransmitter γ-aminobutyric acid (GABA). Since up to 40% of the neurons in the brain utilize GABA as a neurotransmitter, GABA has a significant impact on the excitability of the entire brain. GABA controls the excitability of individual neurons by regulating the conductance of chloride ions across the neuronal membrane. GABA interacts with recognition sites on the GRC, facilitating the flow of chloride ions intracellularly down the electrochemical gradient of the GRC. This intracellular increase in the anion level causes hyperpolarization of the membrane potential across the membrane and reduces the sensitivity of the neuron to excitatory inputs (i.e., the excitability of the neuron decreases). In other words, the higher the chloride ion concentration within the neuron, the lower the excitability and arousal levels of the brain.

[0004] The GRC has been well-documented to be involved in the mediation of anxiety, seizure activity, and sedation. Thus, GABA, and drugs that act like GABA or enhance the action of GABA (e.g., therapeutically useful barbiturates and benzodiazepines (BZ), e.g., Valium®), produce their therapeutically useful effects by interacting with specific control sites on the GRC. Accumulating evidence now suggests that the GRC contains a distinct site for neurosteroids in addition to the benzodiazepine and barbiturate binding sites. See, e.g., Lan, N.C. et al., Neurochem.Res. (1991) 16:347-356.

[0005] Neurosteroids can occur endogenously. The most potent endogenous neurosteroids are 3α-hydroxy-5-reduced pregnan-20-one and 3α-21-dihydroxy-5-reduced pregnan-20-one (metabolites of the hormonal steroids progesterone and deoxycorticosterone, respectively). The ability of these steroid metabolites to alter brain excitability was recognized in 1986 (Majewska, M.D. et al., Science 232:1004-1007 (1986); Harris on, N.L. et al., J Pharmacol. Exp. Ther. 241:346 - 353(1987)). There is a need for novel and improved compounds that act as regulators of brain excitability and as agents for the prevention and treatment of CNS - related diseases. The compounds, compositions, and methods described herein are directed to this purpose.

Prior Art Documents

Non - Patent Documents

[0006]

Non - Patent Document 1

Non - Patent Document 2

Non - Patent Document 3

Summary of the Invention

Means for Solving the Problems

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

[0008] In one aspect, provided herein is a compound of formula (I - I)

Chemical formula

[0009] In one aspect, provided herein is a compound of formula (I - II):

Chemical formula

[0010] In one aspect, provided herein is a compound of formula (I-III):

Chem.

[0011] In one aspect, provided herein is a compound of formula (I-IV):

Chem.

[0012] In some embodiments, the compound is of formula (I-Iea) or formula (I-Iea-1)

Chem.

[0013] In some embodiments, the compound is of formula (I-Ieg) or formula (I-Ieg-1)

Chem.

[0014] In some embodiments, the compound is of formula (I-Ih) or formula (I-Ih-1)

Chem.

[0015] In some embodiments, the compound is of formula (I-Ii) or formula (I-Ii-1)

Chem.

[0016] In some embodiments, the compound is selected from the group consisting of the compounds specified in Table I-1 herein.

[0017] In some embodiments, provided herein is a compound of formula (II-I)

Chemical formula

[0018] In some embodiments, provided herein is a compound of formula (II-II)

Chemical formula

[0019] In some embodiments, provided herein is a compound of formula (II-IIa)

Chemical formula

[0020] In some embodiments, provided herein is a compound of formula (II-III)

Chemical formula

[0021] In some embodiments, the compound of formula (II-I) is a compound of formula (II-Ia), (II-Iaa), (II-Iab), or (II-Iad)

Chemical formula

[0022] In some embodiments, the compound of formula (II-I) is a compound of formula (II-Iba), (II-Ibb), (II-Ibc), or (II-Ibd)

Chemical formula

[0023] In some embodiments, the compound of formula (II-I) is a compound of formula (II-Ica), (II-Icb), (II-Icc), or (II-Icd)

Chemical formula

[0024] In some embodiments, the compound of formula (II-I) is a compound of formula (II-Iea), (II-Ieb), (II-Iec), or (II-Ied)

Chemical formula

[0025] In some embodiments, the compound of formula (II-I) is a compound of formula (II-Iega), (II-I egb), (II-Iegc), or (II-Iegd)

Chemical formula

[0026] In some embodiments, the compound of formula (II-I) is a compound of formula (II-Iha), (II-Ihb), (II-Ihc), or (II-Ihd)

Chemical formula

Chemical formula

[0027] In some embodiments, the compound of formula (II-I) is of formula (II-Iia), (II-Iib), (II-Iic), or (II-Iid)

Chemical formula

[0028] In some embodiments, the compound of formula (II-II) or (II-III) is of formula (II-IIa), (II-IIaa), (II-IIab), (II-IIac), (II-IIad), or (II-IIae)

Chemical formula

[0029] In some embodiments, the compound of formula (II-II) or (II-III) is of formula (II-IIna), (II-IInb), (II-IInc), (II-IInd), or (II-IIne)

Chemical formula

Chemical formula

[0030] In some embodiments, the compound of formula (II-II) or (II-III) is of formula (II-IIma), (II-IImb), (II-IImc), (II-IImd), (II-IIme), (II-IImf), (II-IImg), (II-IImh), (II-IImi), or (II-IImj)

Chemical formula

[0031] In some embodiments, the compound of formula (II-II) or (II-III) is a compound of formula (II-IIpa), (II-IIpb), (II-IIpc), (II-IIpd), (II-IIpe), (II-IIpf), (II-IIpg), (II-IIph), (II -IIpi), (II-IIpj), or (II-IIpk)

Chemical formula

Chemical formula

[0032] In some embodiments, the compound of formula (II-II) or (II-III) is a compound of formula (II-IIwa), (II-IIwb), (II-IIwc), (II-IIwd), (II-IIwe), (II-IIwf), (II-IIwg), (II-IIwh), (II-IIwi), (II-IIwj), or (II-IIwk)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0033] In some embodiments, the compound is selected from the group consisting of the compounds identified in Table II-1 herein. [Table 2-3] [Table 2-4]

[0034] In one aspect, provided herein are pharmaceutically acceptable salts of the compounds described herein (e.g., compounds of formula (I-I), (I-II), (I-III), (I-IV), (II-I), (II-II), or (II-III)).

[0035] In one aspect, provided herein are pharmaceutical compositions comprising a compound described herein (e.g., a compound of formula (I-I), (I-II), (I-III), (I-IV), (II-I), (II-II), or (II-III)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the compounds of the invention are provided in an effective amount in the pharmaceutical composition. In certain embodiments, the compounds of the invention are provided in a therapeutically effective amount. In certain embodiments, the compounds of the invention are provided in a prophylactically effective amount.

[0036] The compounds of the invention as described herein, in certain embodiments, act as, for example, GABA A modulators that act in a positive or negative manner on the GABA AIt is expected to have CNS activity as a regulator of the excitability of the central nervous system (CNS) mediated by the ability to modulate receptors. Thus, in another aspect, a method for treating a CNS-related disorder in a subject in need thereof is provided, the method comprising administering to the subject an effective amount of a compound of the present invention. In certain embodiments, the CNS-related disorder is a sleep disorder, mood disorder, schizophrenia spectrum disorder, spasm disorder, memory and / or cognitive disorder, movement disorder, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disease, substance use disorder and / or withdrawal syndrome, tinnitus, or status epilepticus. In certain embodiments, the CNS-related disorder is depression. In certain embodiments, the CNS-related disorder is postpartum depression. In certain embodiments, the CNS-related disorder is a major depressive disorder. In certain embodiments, the major depressive disorder is a moderate major depressive disorder. In certain embodiments, the major depressive disorder is a severe major depressive disorder. In certain embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered orally. In certain embodiments, the compound is administered for a long term. In certain embodiments, the compound is administered continuously, for example, by continuous intravenous infusion. In embodiments of the present invention, for example, the following items are provided. (Item 1) Formula (I-I): [Chemical formula] a compound of or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2; X is -O-, -N(R X )-, or -S(O) y -, wherein R Xis hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, -S(O)2(R A0 )、-C(O)(R A0 ), or substituted or unsubstituted heteroaryl, where in each case R A0 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and y is 0, 1, or 2; R 3a is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 19 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted C2-C6 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; R 5 is hydrogen or methyl; R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2, -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -NHC( =O)R A1 、 -NHC(=O)OR A1 、 -NHC(=O)SR A1 、 -NHC(=O)N(R A1 )2、 -OS(=O)2R A2 、 -OS(=O)2OR A1 、 -S - S(=O)2R A2 、 -S - S(=O)2OR A1 、 -S(=O)R A2 、 -SO2R A2 、 or -S(=O)2OR A1 wherein, in each case, R A1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when bonded to an oxygen atom, a sulfur protecting group when bonded to a sulfur atom, a nitrogen protecting group when bonded to a nitrogen atom, or two R A1 groups are bonded to form a substituted or unsubstituted heterocyclic ring or heteroaryl ring; R A2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 15a 、 R 15b 、 R 16a 、 and R 16b each are independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 、 -SR A1 、 -N(R A1 )2、 -CN(R A1 )2、 -C(O)R A1 、 -OC(=O)R A1 、 -OC(=O)ORA1 、 -OC(=O)SR A1 、 -OC(=O)N(R A1 )2、 -SC(=O)R A2 、 -SC(=O)OR A1 、 -SC(=O)SR A1 、 -SC(=O)N(R A1 )2、 -NHC(=O)R A1 、 -NHC(=O)OR A1 、 -NHC(=O)SR A1 、 -NHC(=O)N(R A1 )2、 -OS(=O)2R A2 、 -OS(=O)2OR A1 、 -S-S(=O)2R A2 、 -S-S(=O)2OR A1 、 -S(=O)R A2 、 -SO2R A2 、 or -S(=O)2OR A1 wherein, in each case, R A1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when bonded to an oxygen atom, a sulfur protecting group when bonded to a sulfur atom, a nitrogen protecting group when bonded to a nitrogen atom, -SO2R A2 、 -C(O)R A2 or two R A1 groups are joined to form a substituted or unsubstituted heterocyclic ring or heteroaryl ring; R A2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 15a and R 15b or R 16a and R 16b are joined to form an oxo(=O) group; R 1a 、 R 1b 、 R 2a 、 R 2b, R 4a , R 4b , R 7a , R 7b , R 11a , R 11b , R 12a , and R 12b each is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 wherein, in each case, R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when bonded to an oxygen atom, a nitrogen protecting group when bonded to a nitrogen atom, or two R D1 groups are bonded to form a substituted or unsubstituted heterocyclic ring; or R 2a and R 2b , R 4a and R 4b , R 7a and R 7b , R 11a and R 11b , as well as R 12a and R 12b any one of which is bonded to form an oxo(=O) group, where when m is 0, R 1 is substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclyl , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2, -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SRA1 ,-OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2R A2 , -OS(=O)2OR A1 , -S-S(=O)2R A2 , -S-S(=O)2OR A1 , -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 wherein, in each case, R A1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when bonded to an oxygen atom, a sulfur protecting group when bonded to a sulfur atom, a nitrogen protecting group when bonded to a nitrogen atom, or two R A1 groups are joined to form a substituted or unsubstituted heterocyclic ring or heteroaryl ring; R A2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, a compound or a pharmaceutically acceptable salt thereof. (Item 2) Formula (I-II): [Chemical formula] A compound or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2; X is -O-, -N(R X)-, or -S(O) y - and where R X is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, -S(O)2(R A0 ), -C(O)(R A0 ), or substituted or unsubstituted heteroaryl, where in each case R A0 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and y is 0, 1 , or 2; R 3a is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 19 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted C2-C6 alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; R 5 is hydrogen or methyl; R 6a and each of R 6b is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or R 6a and R 6b are joined to form an oxo (=O) group; R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1, -SR A1 , -N(R A1 )2, -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2R A2 , -OS(=O)2OR A1 , -S-S(=O)2R A2 , -S-S(=O)2OR A1 , -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 , where in each case R A1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A1 groups are joined to form a substituted or unsubstituted heterocyclic or heteroaryl ring; R A2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 15a , R 15b , R 16a , and R 16bEach of them is, independently of each other, hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2, -CN(R A1 )2, -C(O)R A1 , -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2R A2 , -OS(=O)2OR A1 , -S-S(=O)2R A2 , -S-S(=O)2OR A1 , -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 wherein, in each case, R A1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when bonded to an oxygen atom, a sulfur protecting group when bonded to a sulfur atom, a nitrogen protecting group when bonded to a nitrogen atom, -SO2R A2 , -C(O)R A2 or two R A1 groups are bonded to form a substituted or unsubstituted heterocyclic ring or heteroaryl ring; R A2is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted is unsubstituted heteroaryl; or R 15a and R 15b or R 16a and R 16b are joined to form an oxo (=O) group; R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 11a 、R 11b 、R 12a 、and R 12b each is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclic, or substituted or unsubstituted alkynyl, -OR D1 、-OC(=O)R D1 、-NH2、-N(R D1 )2、or -NR D1 C(=O)R D1 wherein, in each case, R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when bonded to an oxygen atom, a nitrogen protecting group when bonded to a nitrogen atom, or two R D1 groups are joined to form a substituted or unsubstituted heterocyclic ring; or R 2a and R 2b 、R 4a and R 4b 、R 11a and R 11b 、and R 12a and R 12b any one of which is joined to form an oxo (=O) group, where when m is 0, R1 is a substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2, -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2R A2 , -OS(=O)2OR A1 , -S-S(=O)2R A2 , -S-S(=O)2OR A1 , -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 wherein in each case R A1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when bonded to an oxygen atom, a sulfur protecting group when bonded to a sulfur atom, a nitrogen protecting group when bonded to a nitrogen atom, or two R A1 groups are joined to form a substituted or unsubstituted heterocyclic ring or heteroaryl ring; R A2A compound or a pharmaceutically acceptable salt thereof, which is a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. (Item 3) R 2a and R 2b are each independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclic, or substituted or unsubstituted alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 wherein R D1 in each case is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, a compound as described in item 1 or 2. (Item 4) R 2a and R 2b are each independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2, wherein R D1 in each case is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, a compound as described in any one of items 1 to 3. (Item 5) R 2a and R 2b are each independently hydrogen, substituted or unsubstituted alkyl, -OR D1 , -OC(=O)RD1 、 -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 wherein, in each case, R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, a compound according to any one of items 1 to 4. (Item 6) R 2a and R 2b are both hydrogen, a compound according to any one of items 1 to 5. (Item 7) R 2a and R 2b are each independently hydrogen or substituted or unsubstituted alkyl, a compound according to any one of items 1 to 6. (Item 8) R 2a and R 2b each is independently hydrogen, C1 - C6 alkyl, C1 - C6 haloalkyl, C1 - C6 alkoxy, C1 - C6 alkoxy halo, or -OH, a compound according to any one of items 1 to 7. (Item 9) R 2a and R 2b are -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2, a compound according to any one of items 1 to 8. (Item 10) R 1a or R 1b are each independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclic, or substituted or unsubstituted alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 wherein, in each case, R D1The compound according to any one of items 1 to 9, which is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. (Item 11) R 1a Or R 1b Each is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2, where in each case R D1 Is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, the compound according to any one of items 1 to 10. (Item 12) R 1a Or R 1b Each is independently hydrogen, substituted or unsubstituted alkyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 , where in each case R D1 Is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, the compound according to any one of items 1 to 11. (Item 13) R 1a Or R 1b Each is independently hydrogen, the compound according to any one of items 1 to 12. (Item 14) R 1a Or R 1bThe compound according to any one of items 1 to 13, which is independently hydrogen or substituted or unsubstituted alkyl for each. (Item 15) R 1a or R 1b is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxy halo, or -OH for each, for the compound according to any one of items 1 to 14. (Item 16) R 1a or R 1b is independently -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2 for each, for the compound according to any one of items 1 to 15. (Item 17) R 4a or R 4b is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 wherein in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl for each, for the compound according to any one of items 1 to 16. (Item 18) R 4a and R 4b are independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2 wherein in each case R D1The compound according to any one of items 1 to 17, which is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. (Item 19) R 4a and R 4b are each independently hydrogen, substituted or unsubstituted alkyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 wherein R in each case D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, the compound according to any one of items 1 to 18. (Item 20) R 4a and R 4b both being hydrogen, the compound according to any one of items 1 to 19. (Item 21) R 4a and R 4b are each independently hydrogen or substituted or unsubstituted alkyl, the compound according to any one of items 1 to 20. (Item 22) R 4a and R 4b each is independently hydrogen, C1 - C6 alkyl, C1 - C6 haloalkyl, C1 - C6 alkoxy, C1 - C6 alkoxyhalo, or -OH, the compound according to any one of items 1 to 21. (Item 23) R 4a and R 4b are -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2, the compound according to any one of items 1 to 22. (Item 24) R 11a or R 11bis, independently of each other, hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 wherein R in each case D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, a compound according to any one of items 1 to 23. (Item 25) R 11a or R 11b is, independently of each other, hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2, wherein R in each case D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, a compound according to any one of items 1 to 24. (Item 26) R 11a or R 11b is, independently of each other, hydrogen, substituted or unsubstituted alkyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 wherein R in each case D1The compound according to any one of items 1 to 25, which is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. (Item 27) R 11a Or R 11b The compound according to any one of items 1 to 26, wherein each is independently hydrogen. (Item 28) R 11a Or R 11b The compound according to any one of items 1 to 27, wherein each is independently hydrogen or substituted or unsubstituted alkyl. (Item 29) R 11a Or R 11b Each of which is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxy halo, or -OH, the compound according to any one of items 1 to 28. (Item 30) R 11a Or R 11b Each is independently -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2, the compound according to any one of items 1 to 29. (Item 31) R 15a Or R 15b Each is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclic, or substituted or unsubstituted alkynyl, the compound according to any one of items 1 to 30. (Item 32) R 15a Or R 15b Each is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclic, or substituted or unsubstituted alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1)2. or -NR D1 C(=O)R D1 wherein in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, a compound according to any one of items 1 to 31. (Item 33) R 16a or R 16b is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclic, or substituted or unsubstituted alkynyl, a compound according to any one of items 1 to 32. (Item 34) R 16a or R 16b is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclic, or substituted or unsubstituted alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 wherein in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alken yl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, a compound according to any one of items 1 to 33. (Item 35) R 7a or R 7b is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclic, or substituted or unsubstituted alkynyl, -OR D1, -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 wherein, in each case, R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, a compound according to any one of items 1 to 34. (Item 36) R 7a and R 7b are both hydrogen, a compound according to any one of items 1 to 35. (Item 37) R 7a and R 7b are each independently hydrogen or substituted or unsubstituted alkyl, a compound according to any one of items 1 to 36. (Item 38) R 7a and R 7b each is independently hydrogen, C1 - C6 alkyl, C1 - C6 haloalkyl, C1 - C6 alkoxy, C1 - C6 alkoxy halo, or -OH, a compound according to any one of items 1 to 37. (Item 39) R 7a or R 7b is -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2, a compound according to any one of items 1 to 38. (Item 40) R 5 is hydrogen in the cis position with respect to the 19th position, a compound according to any one of items 1 to 39. (Item 41) R 5 is hydrogen in the trans position with respect to the 19th position, a compound according to any one of items 1 to 40. (Item 42) R 5 is methyl in the cis position with respect to the 19th position, a compound according to any one of items 1 to 41. (Item 43) R 5 is the compound according to any one of Items 1 to 42, wherein R is methyl in the trans position with respect to the C19 position. (Item 44) is the compound according to any one of Items 1 to 43, wherein m is 1. (Item 45) is the compound according to any one of Items 1 to 44, wherein m is 2. (Item 46) R 3a is the compound according to any one of Items 1 to 45, wherein R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. (Item 47) R 3a is the compound according to any one of Items 1 to 46, wherein R is substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. (Item 48) R 3a is the compound according to any one of Items 1 to 47, wherein R is hydrogen or substituted or unsubstituted alkyl. (Item 49) R 3a is the compound according to any one of Items 1 to 48, wherein R is hydrogen. (Item 50) R 3a is the compound according to any one of Items 1 to 48, wherein R is substituted alkyl. (Item 51) R 3a is the compound according to any one of Items 1 to 48, wherein R is unsubstituted alkyl. (Item 52) R 3a is the compound according to any one of Items 1 to 48, wherein R is hydrogen or methyl. (Item 53) R 3a is the compound according to any one of Items 1 to 48, wherein R is methyl. (Item 54) R 19The compound according to any one of items 1 to 48, wherein it is ethyl. (Item 55) R 19 The compound according to any one of items 1 to 48, wherein it is hydrogen. (Item 56) R 19 The compound according to any one of items 1 to 55, wherein it is substituted alkyl. (Item 57) R 19 The compound according to any one of items 1 to 55, wherein it is unsubstituted alkyl. (Item 58) R 19 The compound according to any one of items 1 to 55, wherein it is substituted C2-C6 alkyl. (Item 59) R 19 The compound according to any one of items 1 to 55, wherein it is unsubstituted C2-C6 alkyl. (Item 60) R 19 The compound according to any one of items 1 to 55, wherein it is substituted C2-C6 alkenyl. (Item 61) R 19 The compound according to any one of items 1 to 55, wherein it is unsubstituted C2-C6 alkenyl. (Item 62) R 19 The compound according to any one of items 1 to 55, wherein it is substituted C2-C6 alkynyl. (Item 63) R 6a and R 6b The compound according to any one of items 1 to 62, wherein R and R are independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. (Item 64) R 6a and R 6b The compound according to any one of items 2 to 63, wherein R and R are independently hydrogen or substituted alkyl. (Item 65) R 6a and R6b The compound according to any one of items 2 to 63, wherein both are hydrogen. (Item 66) R 6a is halo or alkyl, and R 6b is hydrogen, the compound according to any one of items 2 to 63. (Item 67) R 6a and R 6b both are halo, the compound according to any one of items 2 to 63. (Item 68) R 6a and R 6b both are alkyl, the compound according to any one of items 2 to 63. (Item 69) R 12a and R 12b are each independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 wherein in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, the compound according to any one of items 1 to 68. (Item 70) R 12a and R 12b are each independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2, wherein in each case R D1The compound according to any one of items 1 to 69, which is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. (Item 71) R 12a and R 12b are each independently hydrogen, substituted or unsubstituted alkyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 wherein R D1 in each case is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, the compound according to any one of items 1 to 70. (Item 72) R 12a and R 12b both being hydrogen, the compound according to any one of items 1 to 71. (Item 73) R 12a and R 12b are each independently hydrogen or substituted or unsubstituted alkyl, the compound according to any one of items 1 to 72. (Item 74) R 12a and R 12b each is independently hydrogen, C1 - C6 alkyl, C1 - C6 haloalkyl, C1 - C6 alkoxy, C1 - C6 alkoxy halo, or -OH, the compound according to any one of items 1 to 73. (Item 75) R 12a and R 12b are -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2, the compound according to any one of items 1 to 74. (Item 76) R 12a and R 12bThe compound according to any one of items 1 to 75, wherein both are hydrogen. (Item 77) R 12a and R 12b together form an oxo, the compound according to any one of items 1 to 76. (Item 78) R 12a and R 12b are each independently hydrogen or substituted or unsubstituted alkyl, the compound according to any one of items 1 to 77. (Item 79) R 12a and R 12b are each H, the compound according to any one of items 1 to 78. (Item 80) R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, the compound according to any one of items 1 to 79. (Item 81) R 1 is [Chemical formula] wherein in each case R 20 is independently halogen, -NO2, -CN, -OR GA , -N(R GA )2, -C(=O)R GA , -C(=O)OR GA , -OC(=O)R GA , -OC(=O)OR GA , -C(=O)N(R GA )2, -N(R GA )C(=O)R GA , -OC(=O)N(R GA )2, -N(R GA )C(=O)OR GA , -S(=O)2R GA , -S(=O)2OR GA, -OS(=O)2R GA , -S(=O)2N(R GA )2, or -N(R GA )S(=O)2R GA ; substituted or unsubstituted C 1~6 alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 alkynyl, substituted or unsubstituted C 3~4 carbocyclic, substituted or unsubstituted 3- to 4-membered heterocyclyl, or optionally two R GA together with the intervening atom form a substituted or unsubstituted 3- to 4-membered carbocyclic or heterocyclic ring; wherein, in each case, R GA is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 alkynyl, substituted or unsubstituted C 3~6 carbocyclic, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when bonded to oxygen, a nitrogen protecting group when bonded to nitrogen, or two R groups together with the intervening atom form a substituted or unsubstituted carbocyclic or heterocyclic ring; GA e is 0, 1, 2, 3, 4, or 5, and n is 0, 1, 2, 3, 4, or 5, a compound according to any one of items 1 to 80. (Item 82) (Item 82) R 1 is [Chemical formula] and wherein, in each case, R 20 is independently halogen, -NO2, -CN, -OR GA , -N(R GA )2, -C(=O)R GA , -C(=O)OR GA , -OC(=O)R GA , -OC(=O)OR GA , -C(=O)N(RGA ) 2, -N(R GA )C(=O)R GA , -OC(=O)N(R GA )2, -N(R GA )C(=O)OR GA , -S(=O)2R GA , -S(=O)2OR GA , -OS(=O)2R GA , -S(=O)2N(R GA )2, or -N(R GA )S(=O)2R GA ; substituted or unsubstituted C 1~6 alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 alkynyl, substituted or unsubstituted C 3~4 carbocyclic, substituted or unsubstituted 3- to 4-membered heterocyclyl, or optionally two R GA together with the intervening atom form a substituted or unsubstituted 3- to 4-membered carbocyclic or heterocyclic ring; wherein, in each case, R GA is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 alkynyl, substituted or unsubstituted C 3~6 carbocyclic, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when bonded to oxygen, a nitrogen protecting group when bonded to nitrogen, or two R GA groups together with the intervening atom form a substituted or unsubstituted carbocyclic or heterocyclic ring; e is 0, 1, 2, 3, 4, or 5, and n is 0, 1, 2, 3, 4, or 5, a compound according to any one of items 1 to 81. (Item 83) The compound is of formula (I-Iea) or formula (I-Iea-1)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical Structure

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Mode for Carrying Out the Invention

[0037] Detailed Description of Specific Embodiments of the Invention As generally described herein, the present invention provides compounds designed to act as, for example, GABA A modulators. In certain embodiments, such compounds are contemplated to be useful as therapeutic agents for treating CNS-related disorders (such as the disorders described herein, such as depression, such as postpartum depression or major depressive disorder).

[0038] Definitions Chemical Definitions The definitions of specific functional groups and chemical terms are described in detail below. Chemical elements are specified according to the Periodic Table of the Elements (CAS version, Handbook of Chemistry and Physics, 75th Edition, inside cover), and specific functional groups are generally defined as described therein. Further, the general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0039] Isomers (e.g., stereoisomers) can be isolated from mixtures by methods known to those skilled in the art (including chiral high performance liquid chromatography (HPLC) as well as the formation of chiral salts); or the preferred isomers can be prepared by asymmetric synthesis. For example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereoch See Chemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, editor, Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention further includes the compounds described herein as individual isomers substantially free of other isomers and / or as mixtures of various isomers.

[0040] "Stereoisomers": It should also be understood that compounds having the same molecular formula but differing in the nature of the atoms or the order of bonding or the arrangement of atoms in space are called "isomers". Isomers that differ in the arrangement of atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereomers", and those that are mirror images that cannot be superimposed on each other are called "enantiomers". For example, if a compound has an asymmetric center, it is bonded to four different groups and a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and are represented by the R and S ordering rules of Cahn and Prelog or by the way the molecule rotates the plane of polarization and are designated as dextrorotatory or levorotatory (i.e., the (+) or (-)-isomers, respectively). Chiral compounds can exist either as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0041] As used herein, a pure enantiomeric compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., enantiomeric excess). In other words, a compound of the "S" form is substantially free of the compound of the "R" form and thus has an "R" enantiomeric excess. The terms "enantiomerically pure" or "pure enantiomer" mean that the compound contains more than 75%, more than 80%, more than 85%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 98.5%, more than 99%, more than 99.2%, more than 99.5%, more than 99.6%, more than 99.7%, more than 99.8% or more than 99.9% enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0042] In the compositions provided herein, an enantiomerically pure compound may be present with other active or inactive ingredients. For example, a pharmaceutical composition containing an enantiomerically pure R-position / center / carbon compound may contain, for example, about 90% excipient and about 10% enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R-compound in such a composition may contain, for example, at least about 95% R-compound and at most about 5% S-compound, based on the total weight of the compound. For example, a pharmaceutical composition containing an enantiomerically pure S-compound may contain, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S-compound in such a composition may contain, for example, at least about 95% S-compound and at most about 5% R-compound, based on the total weight of the compound. In certain embodiments, the active ingredient may be formulated with a small amount of excipient or carrier or may be formulated without an excipient or carrier.

[0043] As used herein, the term "diastereomeric purity" refers to the amount of a compound having the indicated absolute stereochemistry, expressed as a percentage of the total amount of the indicated compound and its diastereomers. The term "diastereomerically pure" means that the compound contains more than 75%, more than 80%, more than 85%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 98.5%, more than 99%, more than 99.2%, more than 99.5%, more than 99.6%, more than 99.7%, more than 99.8%, or more than 99.9% diastereomers. Methods for determining diastereomeric purity and enantiomeric purity are well known in the art. Diastereomeric purity can be determined by any analytical method (such as high performance liquid chromatography (HPLC)) that can quantitatively distinguish between the compound and its diastereomers.

[0044] The articles "a" and "an" can be used herein to refer to one or more (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.

[0045] When a range of values is recited, it is intended to include each value and sub-range within that range. For example, "C 1~6 alkyl" includes C1, C2, C3, C4, C5, C6, C 1~6 、C 1~5 、C 1~4 、C 1~3 、C 1~2 、C 2~6 、C 2~5 、C 2~4 、C 2~3 、C 3~6 、C 3~5 、C 3~4 、C 4~6 、C 4~5 、and C5~6 is intended to include alkyls.

[0046] The following terms are intended to have the meanings presented below with respect thereto and are useful in understanding the specification and the intended scope of the invention.

[0047] "Alkyl" refers to a radical of a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1~20 alkyl"). In some embodiments, the alkyl group has 1 to 12 carbon atoms ("C 1~12 alkyl"). In some embodiments, the alkyl group has 1 to 10 carbon atoms ("C 1~10 alkyl"). In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C 1~9 alkyl"). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1~8 alkyl"). In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1~7 alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C 1~6 alkyl", also referred to herein as "lower alkyl"). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C 1~5 alkyl"). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C 1~4 alkyl"). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1~3 alkyl"). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1~2 alkyl"). In some embodiments, the alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2~6 alkyl"). C 1~6Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanil (C5), tertiary amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc. Unless otherwise specified, each occurrence of an alkyl group is independently optionally substituted, i.e., unsubstituted (“unsubstituted alkyl”) or substituted with one or more substituents; for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (“substituted alkyl”). In certain embodiments, the alkyl group is unsubstituted C 1~10 alkyl (e.g., -CH3). In certain embodiments, the alkyl group is substituted C 1~10 alkyl. Common abbreviations for alkyl include Me (-CH3), Et (-CH2CH3) , iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2).

[0048] "Alkylene" refers to an alkyl group from which two hydrogens have been removed to give a divalent radical, which may be substituted or unsubstituted. Examples of unsubstituted alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), and hexylene (-CH2CH2CH2CH2CH2CH2-). Exemplary substituted alkylene groups substituted with one or more alkyl (methyl) groups include, but are not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, and -CH2CH2C(CH3)2-). When a range or number of carbons is given for a particular alkylene group, it is understood that the recited range or number refers to the range or number of carbons in the divalent carbon straight chain. The alkylene group may be substituted or unsubstituted with one or more substituents described herein.

[0049] "Alkenyl" refers to a radical of a straight-chain or branched-chain hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) ("C 2~20 alkenyl"). In certain embodiments, alkenyl does not contain any triple bonds. In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C 2~10 alkenyl"). In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C 2~9"(alkenyl). In some embodiments, the alkenyl group has from 2 to 8 carbon atoms ("C 2~8 alkenyl). In some embodiments, the alkenyl group has from 2 to 7 carbon atoms ("C 2~7 alkenyl). In some embodiments, the alkenyl group has from 2 to 6 carbon atoms ("C 2~6 alkenyl). In some embodiments, the alkenyl group has from 2 to 5 carbon atoms ("C 2~5 alkenyl). In some embodiments, the alkenyl group has from 2 to 4 carbon atoms ("C 2~4 alkenyl). In some embodiments, the alkenyl group has from 2 to 3 carbon atoms ("C 2~3 alkenyl). In some embodiments, the alkenyl group has 2 carbon atoms ("C2 alkenyl"). One or more carbon-carbon double bonds may be internal (e.g., 2-butenyl) or terminal (e.g., 1-butenyl). C 2~4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. C 2~6 Examples of alkenyl groups include the above-described C 2~4 alkenyl groups, as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrieneyl (C8), and the like. Unless otherwise specified, each occurrence of an alkenyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, the alkenyl group is unsubstituted C 2~10 alkenyl. In certain embodiments, the alkenyl group is substituted C 2~10 alkenyl.

[0050] "Alkynyl" refers to a radical of a linear or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) ( "C 2~20 alkynyl"). In certain embodiments, alkynyl does not contain any double bonds. In some embodiments, the alkynyl group has 2 to 10 carbon atoms ( "C 2~10 alkynyl"). In some embodiments, the alkynyl group has 2 to 9 carbon atoms ( "C 2~9 alkynyl"). In some embodiments, the alkynyl group has 2 to 8 carbon atoms ( "C 2~8 alkynyl"). In some embodiments, the alkynyl group has 2 to 7 carbon atoms ( "C 2~7 alkynyl"). In certain embodiments, the alkynyl group has 2 to 6 carbon atoms ( "C 2~6 alkynyl"). In certain embodiments, the alkynyl group has 2 to 5 carbon atoms ( "C 2~5 alkynyl"). In certain embodiments, the alkynyl group has 2 to 4 carbon atoms ( "C 2~4 alkynyl"). In certain embodiments, the alkynyl group has 2 to 3 carbon atoms ( "C 2~3 alkynyl"). In certain embodiments, the alkynyl group has 2 carbon atoms ( "C2 alkynyl"). One or more carbon-carbon triple bonds can be internal (e.g., 2-butynyl) or terminal (e.g., 1-butynyl). C 2~4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. C 2~6 Examples of alkenyl groups include the above-described C 2~4Alkynyl groups, and examples include pentynyl (C5), hexynyl (C6), etc. Further examples of alkynyl include heptynyl (C7), octynyl (C8), etc. Unless otherwise specified, each occurrence of an alkynyl group is independently optionally substituted, i.e., unsubstituted ( "unsubstituted alkynyl") or substituted with one or more substituents; for example, substituted with 1 to 5 substituents, 1 to 3 substituents or 1 substituent ( "substituted alkynyl"). In certain embodiments, the alkynyl group is unsubstituted C 2~10 is alkynyl. In certain embodiments, the alkynyl group is substituted C 2~10 is alkynyl.

[0051] As used herein, the term "heteroalkyl" further includes one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, where the one or more heteroatoms described above are inserted between adjacent carbon atoms in the parent carbon chain and / or one or more heteroatoms are inserted between a carbon atom and the parent molecule (i.e., between the bonding points), and refers to an alkyl group as defined herein. In certain embodiments, a heteroalkyl group refers to a saturated group having 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms ( "heteroC 1~10 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms ( "heteroC 1~9 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms ( "heteroC 1~8 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms ( "heteroC 1~7 alkyl"). In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ( "heteroC 1~6"(alkyl)". In some embodiments, the heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("heteroC 1~5 alkyl)". In some embodiments, the heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms ("heteroC 1~4 alkyl)". In some embodiments, the heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom ("heteroC 1~3 alkyl)". In some embodiments, the heteroalkyl group is a saturated group having 1 to 2 car bon atoms and 1 heteroatom ("heteroC 1~2 alkyl)". In some embodiments, the heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroC1 alkyl"). In some embodiments, the heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms ("heteroC 2~6 alkyl)". Unless otherwise specified, in each case the heteroalkyl group is independently unsubstituted ("unsubstituted heteroalkyl") or substituted with one or more substituents ("substituted heteroalkyl"). In certain embodiments, the heteroalkyl group is unsubstituted heteroC 1~10 alkyl. In certain embodiments, the heteroalkyl group is substituted heteroC 1~10 alkyl.

[0052] "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 π electrons shared in a cyclic arrangement) in which 6 to 14 ring carbon atoms and 0 heteroatoms are provided in the aromatic ring system ("C 6~14 aryl)". In some embodiments, the aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has 10 ring carbon atoms ("C 10"Aryl"; for example, naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14 "Aryl"; for example, anthracyl). "Aryl" also includes a ring system in which one or more aryl rings as defined above are condensed with a carbocyclic group or a heterocyclic group, where the bonding radical or the bonding point is present on the aryl ring, and in such a case, the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, preiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. In particular, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each occurrence of an aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, the aryl group is unsubstituted C 6~14 aryl. In certain embodiments, the aryl group is substituted C 6~14 aryl.

[0053] In certain embodiments, the aryl group is substituted with one or more groups selected from halo, C1-C8 alkyl, C1-C8 haloalkyl, cyano, hydroxy, C1-C8 alkoxy, and amino.

[0054] Examples of representative substituted aryls include the following:

Chemical formula

[0055] "Condensed aryl" refers to aryl in which two of its ring carbons are shared with a second aryl ring, heteroaryl ring, carbocyclic ring or heterocyclic ring.

[0056] "Heteroaryl" refers to a radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) in which ring carbon atoms and 1 to 4 ring heteroatoms are provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In a heteroaryl group containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom when the valence allows. The heteroaryl bicyclic ring system can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused to one or more carbocyclic or heterocyclic groups, where the point of attachment is on the heteroaryl ring, and in such cases, the number of ring members continues to refer to the number of ring members within the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused to one or more aryl groups, where the point of attachment is on the aryl ring or the heteroaryl ring, and in such cases, the number of ring members refers to the number of ring members within the fused (aryl / heteroaryl) ring system. For a bicyclic heteroaryl group in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on the ring having a heteroatom (e.g., 2-indolyl) or on the ring not containing a heteroatom (e.g., 5-indolyl).

[0057] In some embodiments, the heteroaryl group is a 5- to 10-membered aromatic ring system in which ring carbon atoms and 1 to 4 ring heteroatoms are provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "5- to 10-membered heteroaryl"). In some embodiments, the heteroaryl group is a 5- to 8-membered aromatic ring system in which ring carbon atoms and 1 to 4 ring heteroatoms are provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heteroaryl"). In some embodiments, the heteroaryl group is a 5- to 6-membered aromatic ring system in which ring carbon atoms and 1 to 4 ring heteroatoms are provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "5- to 6-membered heteroaryl"). In some embodiments, the 5- to 6-membered heteroaryl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each occurrence of the heteroaryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, the heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0058] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-fused bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-fused bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0059] Examples of representative heteroaryls include the following: [Chemical Formula] are included, where each Z is carbonyl, N, NR65 , O, and S; R 65 is independently hydrogen, C1-C8 alkyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl.

[0060] "Carbocyclyl" or "carbocyclic" refers to a radical of a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms ("C 3~10 carbocyclyl") and 0 heteroatoms in the non-aromatic ring system. In some embodiments, the carbocyclyl group has 3 to 8 ring carbon atoms ("C 3~8 carbocyclyl"). In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 carbocyclyl"). In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 carbocyclyl"). In some embodiments, the carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10 carbocyclyl"). Exemplary C 3~6 carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. Exemplary C 3~8 carbocyclyl groups include the above-mentioned C 3~6 carbocyclyl groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), etc. Exemplary C 3~10 carbocyclyl groups include the above-mentioned C 3~8 carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10) Cyclodecenyl (C 10 ) Octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ) Spiro[4.5]decanyl (C 10 ) and the like, but not limited thereto. When the foregoing examples are illustrated, in certain embodiments, the carbocyclic group is monocyclic (“monocyclic carbocyclic”), or includes a fused ring system, a bridged ring system or a spiro ring system (e.g., a bicyclic system (“bicyclic carbocyclic”)), and may be saturated or partially unsaturated. “Carbocyclic” also includes a ring system in which one or more aryl groups or heteroaryl groups are fused to a carbocyclic ring as defined above, where the point of attachment is on the carbocyclic ring, and in such cases, the number of carbons continues to refer to the number of carbons in the carbocyclic ring system. Unless otherwise specified, each occurrence of a carbocyclic group is independently optionally substituted, i.e., unsubstituted (“unsubstituted carbocyclic”) or substituted with one or more substituents (“substituted carbocyclic”). In certain embodiments, the carbocyclic group is unsubstituted C 3~10 carbocyclic. In certain embodiments, the carbocyclic group is substituted C 3~10 carbocyclic.

[0061] In some embodiments, “carbocyclic” is a monocyclic saturated carbocyclic group having 3 to 10 ring carbon atoms (“C 3~10 cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms (“C 3~8 cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms (“C 3~6 cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 6 ring carbon atoms (“C 5~6 cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 10 ring carbon atoms (“C 5~10 cycloalkyl”). C 5~6Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). C 3~6 Examples of cycloalkyl groups include the above-mentioned C 5~6 cycloalkyl groups, as well as cyclopropyl (C3) and cyclobutyl (C4). C 3~8 Examples of cycloalkyl groups include the above-mentioned C 3~6 cycloalkyl groups, as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each occurrence of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, the cycloalkyl group is unsubstituted C 3~10 cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C 3~ 10 cycloalkyl.

[0062] "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, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("3- to 10-membered heterocyclyl"). In a heterocyclyl group containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom when the valence allows. The heterocyclyl group can be a monocyclic ring system ("monocyclic heterocyclyl") or a fused ring system, a bridged ring system or a spiro ring system (e.g., a bicyclic system ("bicyclic heterocyclyl")), and can be saturated or partially unsaturated. The heterocyclyl bicyclic ring system can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes a ring system in which a heterocyclyl ring as defined above is fused to one or more carbocyclic groups, where the point of attachment is on the carbocyclic or heterocyclyl ring, or on a ring system in which a heterocyclyl ring as defined above is fused to one or more aryl groups or heteroaryl groups, where the point of attachment is on the heterocyclyl ring, and in such cases, the number of ring members continues to refer to the number of ring members within the heterocyclyl ring system. Unless otherwise specified, each occurrence of heterocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0063] In some embodiments, the heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 10-membered heterocyclyl”). In some embodiments, the heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heterocyclyl”). In some embodiments, the heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heterocyclyl”). In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0064] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiirenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrol-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, Examples include, but are not limited to, dithianyl and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic rings) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocyclic rings) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0065] The term "nitrogen-containing heterocyclyl" group means a 4- to 7-membered non-aromatic cyclic group containing at least one nitrogen atom (e.g., but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazine (such as N-methylpiperazine)). Specific examples include azetidine, piperidone, and piperazone.

[0066] When used to describe a compound or a group present on a compound, "hetero" means that one or more carbon atoms in the compound or group are replaced by heteroatoms of nitrogen, oxygen, or sulfur. Hetero can be applied to any of the above hydrocarbyl groups (alkyl having 1 to 5, especially 1 to 3 heteroatoms, such as heteroalkyl, cycloalkyl, such as heterocyclyl, aryl, such as heteroaryl, and cycloalkenyl, such as cycloheteroalkenyl, etc.).

[0067] "Acyl" means -C(O)R 20 referring to a radical, where R 20 is hydrogen, substituted or unsubstituted alkyl as defined herein, 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. "Alkanoyl" is an acyl group where R 20 is a group other than hydrogen. Representative acyl groups include formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), --C(O)-C1-C8 alkyl, -C(O)-(CH2) t (C6-C 10 aryl), -C(O)-(CH2) t (5- to 10-membered heteroaryl), -C(O)-(CH2) t (C3-C 10 cycloalkyl) and -C(O)-(CH2) t (4- to 10-membered heterocyclyl) (t is an integer from 0 to 4), but are not limited thereto. In certain embodiments, R 21 is C1-C8 alkyl substituted with halo or hydroxy; or C3-C 10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10Aryl, arylalkyl, 5- to 10-membered heteroaryl or heteroarylalkyl (each of which is unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy substituted).

[0068] "Alkoxy" refers to -OR 29 group, where R 29 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. Specific alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1,2-dimethylbutoxy. Specific alkoxy groups are lower alkoxy, i.e., having 1 to 6 carbon atoms. Further specific alkoxy groups have 1 to 4 carbon atoms.

[0069] In certain embodiments, R 29 is amino, substituted amino, C6-C 10 aryl, aryloxy, carboxyl, cyano, C3-C 10 cycloalkyl, 4- to 10-membered heterocyclic, halogen, 5- to 10-membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2- and aryl-S(O)2- a group having one or more substituents selected from the group consisting of, for example, 1 to 5 substituents, particularly 1 to 3 substituents, particularly 1 substituent. Exemplary "substituted alkoxy" groups include -O-(CH2) t (C6-C 10 aryl), -O-(CH2) t (5- to 10-membered heteroaryl), -O-(CH2) t (C3-C10 (cycloalkyl) and -O-(CH2) t (4- to 10-membered heterocyclyl), among others, and is not limited thereto. Here, t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl or heterocyclyl group present may itself be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy. Particularly exemplary "substituted alkoxy" groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH and -OCH2CH2NMe2.

[0070] "Amino" refers to the -NH2 radical.

[0071] The "oxo" group refers to -C(=O)-.

[0072] "Substituted amino" refers to an amino group of the formula -N(R 38 )2, where R 38 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or an amino protecting group, where at least one of R 38 is not hydrogen. In certain embodiments, each R 38 is independently hydrogen, C1-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl or C3-C 10 cycloalkyl; or C1-C8 alkyl substituted with halo or hydroxy; C3-C8 alkenyl substituted with halo or hydroxy; C3-C8 alkynyl substituted with halo or hydroxy, or -(CH2) t (C6-C 10 aryl), -(CH2) t(5 - to 10 - membered heteroaryl), -(CH2) t (C3 - C 10 cycloalkyl) or -(CH2) t (4 - to 10 - membered heterocyclyl), where t is an integer from 0 to 8, and each of them is unsubstituted C1 - C4 alkyl, halo, unsubstituted C1 - C4 alkoxy, unsubstituted C1 - C4 haloalkyl, unsubstituted C1 - C4 hydroxyalkyl, or substituted by unsubstituted C1 - C4 haloalkoxy or hydroxy; or both R 38 groups are joined to form an alkylene group.

[0073] Exemplary "substituted amino" groups include -NR 39 -C1 - C8 alkyl, -NR 39 -(CH2) t (C6 - C 10 aryl), -NR 39 -(CH2) t (5 - to 10 - membered heteroaryl), -NR 39 -(CH2) t (C3 - C 10 cycloalkyl) and -NR 39 -(CH2) t (4 - to 10 - membered heterocyclyl), including but not limited to, where t is an integer from 0 to 4, for example, 1 or 2, and each R 39 is independently hydrogen or represents C1-C8 alkyl; any alkyl group present may itself be substituted by halo, substituted or unsubstituted amino or hydroxy; any aryl, heteroaryl, cycloalkyl or heterocyclyl group present may itself be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy. To avoid misunderstanding, the term "substituted amino" includes alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino and substituted dialkylamino groups as defined below. Substituted amino includes both mono-substituted amino groups and di-substituted amino groups.

[0074] "Carboxy" refers to the -C(O)OH radical.

[0075] "Cyano" refers to the -CN radical.

[0076] "Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, the halo group is either fluoro or chloro.

[0077] "Haloalkyl" refers to an alkyl radical in which the alkyl group is substituted by one or more halogens. Typical haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, and tetrafluoroethyl.

[0078] "Hydroxy" refers to the -OH radical.

[0079] "Nitro" refers to the -NO2 radical.

[0080] "Thio-keto" refers to the =S group.

[0081] Alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, 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" carbocyclic, "substituted" or "unsubstituted" heterocyclic, "substituted" or "unsubstituted" aryl or "substituted" or "unsubstituted" heteroaryl groups). Generally, the term "substituted", whether or not preceded by the term "optionally", means that at least one hydrogen present on a given group (e.g., a carbon or nitrogen atom) is replaced by an acceptable substituent, e.g., a substituent which, when substituted, results in a stable compound, i.e., a compound that does not undergo spontaneous transformation (e.g., by rearrangement, cyclization, elimination or other reactions). Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when two or more positions in any given structure are substituted, the substituents are the same or different at each position. The term "substituted" is intended to include substitution by all acceptable substituents of organic compounds, substitution by any of the substituents described herein that form stable compounds. The present invention contemplates any and all such combinations in order to arrive at stable compounds. For the purposes of the present invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents as described herein that satisfy the valence of the heteroatom and thus form a stable moiety.

[0082] Exemplary carbon atom substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc)R bb 、 -SH, -SR aa 、 -SSR cc 、 -C(=O)R aa 、 -CO2H, -CHO, -C(OR cc )2, -CO2R aa 、 -OC(=O)R aa 、 -OCO2R aa 、 -C(=O)N(R bb )2, -OC(=O)N(R bb )2, -NR bb C(=O)R aa 、 -NR bb CO2R aa 、 -NR bb C(=O)N(R bb )2, -C(=NR bb )R aa 、 -C(=NR bb )OR aa 、 -OC(=NR bb )R aa 、 -OC(=NR bb )OR aa 、 -C(=NR bb )N(R bb )2, -OC(=NR bb )N(R bb )2, -NR bb C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa 、 -NR bb SO2R aa 、 -SO2N(R bb )2, -SO2R aa 、 -SO2OR aa 、 -OSO2R aa 、 -S(=O)R aa 、 -OS(=O)R aa 、 -Si(R aa )3, -OSi(R aa )3 - C(=S)N(R bb )2, -C(=O)SR aa 、 -C(=S)SR aa 、 -SC(=S)SR aa 、 -SC(=O)SR aa 、 -OC(=O)SR aa 、 -SC(=O)ORaa 、 -SC(=O)R aa 、 -P(=O)2R aa 、 -OP(=O)2R aa 、 -P(=O)(R aa )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc )、 C 1~10 alkyl, C 1~10 haloalkyl, C 2~10 alkenyl, C 2~10 alkynyl, C 3~10 carbocyclic, 3 - to 14 - membered heterocyclic, C 6~14 aryl and 5 - to 14 - membered heteroaryl are included, but not limited thereto, where each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa 、 =NNR bb C(=O)OR aa 、 =NNR bb S(=O)2R aa 、 =NR bb 、 or =NOR cc ; R aaEach existence of is independently C 1~10 alkyl, C 1~10 haloalkyl, C 2~10 alkenyl, C 2~10 alkynyl, C 3~10 carbocyclic, 3- to 14-membered heterocyclic, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R aa groups are linked to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups; R bb Each existence of is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1~10 alkyl, C 1~10 haloalkyl, C 2~10 alkenyl, C 2~10 alkynyl, C 3~10 carbocyclic, 3- to 14-membered heterocyclic, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R bbThe groups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups; R cc each occurrence of which is independently hydrogen, C 1~10 alkyl, C 1~10 haloalkyl, C 2~10 alkenyl, C 2~10 alkynyl, C 3~10 carbocyclic, 3- to 14-membered heterocyclyl, C 6~14 aryl and 5- to 14-membered heteroaryl, or two R cc groups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups; R dd each occurrence of which is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff) 2, -C(=NR ff ) OR ee , -OC(=NR ff ) R ee , -OC(=NR ff ) OR ee , -C(=NR ff ) N(R ff ), 2, -OC(=NR ff ) N(R ff ), 2, -NR ff C(=NR ff ) N(R ff ), 2, -NR ff SO2R ee , -SO2N(R ff ), 2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O) R ee , -Si(R ee ) 3, -OSi(R ee ) 3, -C(=S) N(R ff ) 2, -C(=O) SR ee , -C(=S) SR ee , -SC(=S) SR ee , -P(=O) 2R ee , -P(=O) (R ee ) 2, -OP(=O) (R ee ) 2, -OP(=O) (OR ee ) 2, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 carbocyclic, 3 - to 10 - membered heterocyclic, C 6~10 aryl, 5 - to 10 - membered heteroaryl, selected from, where each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups; or two geminal R dd substituents can together form =O or =S; R ee each occurrence of which is independently C 1~6 alkyl, C 1~6 haloalkyl, C2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclic, C 6~10 Selected from aryl, 3- to 10-membered heterocyclic and 3- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R gg groups;

[0083] R ff each occurrence of which is independently hydrogen, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 carbocyclic, 3- to 10-membered heterocyclic, C 6~10 aryl and 5- to 10-membered heteroaryl, or two R ff groups are linked to form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R gg groups;

[0084] R gg each occurrence of which is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C 1~6 alkyl)3 + X - 、-NH(C 1~6 alkyl)2 + X - 、-NH2(C 1~6 alkyl) + X - 、-NH3 + X - 、-N(OC 1~6 alkyl)(C 1~6 alkyl), -N(OH)(C1~6 alkyl), -NH(OH), -SH, -SC 1~6 alkyl, -SS(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -CO2H, -CO2(C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -C(=O)NH2, -C(=O)N(C 1~6 alkyl)2, -OC(=O)NH(C 1~6 alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1~6 alkyl), -OC(=NH)(C 1~6 alkyl), -OC(=NH)OC 1~6 alkyl, -C(=NH)N(C 1~6 alkyl)2, -C(=NH)NH(C 1~6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1~6 alkyl)2, -OC(NH)NH(C 1~6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1~6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 alkyl), -SO2NH2, -SO2C 1~6 alkyl, -SO2OC 1~6 alkyl, -OSO2C 1~6 alkyl, -SOC 1~6 alkyl, -Si(C 1~6 alkyl)3, -OSi(C 1~6 alkyl)3-C(=S)N(C 1~6 alkyl)2, C(=S)NH(C 1~6(alkyl), C(=S)NH2, -C(=O)S(C 1~6 (alkyl), -C(=S)SC 1~6 alkyl, -SC(=S)SC 1~6 alkyl, -P(=O)2(C 1~6 (alkyl), -P(=O)(C 1~6 (alkyl)2, -OP(=O)(C 1~6 (alkyl)2, -OP(=O)(OC 1~6 (alkyl)2, C 1~6 alkyl, C 1~6 haloalkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 carbocyclic, C 6~10 aryl, 3- to 10-membered heterocyclic, 5- to 10-membered heteroaryl; or two geminal R gg substituents can together form =O or =S; where X - is a counterion.

[0085] A "counterion" or "anionic counterion" is a negatively charged group that associates with a cationic quaternary amino group to maintain electrical neutrality. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , OH - , H2PO4 - , HSO4 - , sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.) and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0086] These and other exemplary substituents are described in detail in the Detailed Description and the claims. The present invention is not intended to be limited by the exemplary listing of substituents above by any means.

[0087] Other Definitions As used herein, the term "modulate" refers to inhibition or potentiation of GABA A receptor function. A "modulator" (e.g., a modulator compound) can be, for example, an agonist, partial agonist, antagonist, or partial antagonist of a GABA A receptor.

[0088] "Pharmaceutically acceptable" means approved or approvable by a federal or state regulatory agency, or the corresponding agency of a country outside the United States, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals (more specifically, humans).

[0089] "Pharmaceutically acceptable salt" refers to salts of the compounds of the present invention that are pharmaceutically acceptable and have the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and can be inorganic acid addition salts or organic acid addition salts and inorganic base addition salts or organic base addition salts. Specifically, such salts include (1) those formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or organic acids, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hyd Acid addition salts formed with roxybenzoyl)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, etc.; or (2) the acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or salts formed when coordinated with an organic base, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Examples of salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.; and when the compound contains a basic functional group, salts of non-toxic organic acids or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion for an acidic functional group. Such cations are exemplified by sodium cation, potassium cation, calcium cation, magnesium cation, ammonium cation, tetraalkylammonium cation, etc. See, for example, Berge et al., J. Pharm. Sci. (1977) 66(1):1-79.

[0090] The term "prodrug" is intended to include a therapeutically inactive compound that is converted to the therapeutically active agent of the present invention under physiological conditions. One method of preparing a prodrug is to design a hydrolyzable or cleavable moiety at a targeted in vivo site of action such that the desired molecule appears under physiological conditions and then produces its therapeutic effect. In certain embodiments, the prodrug is converted by the enzymatic activity of the subject.

[0091] In an alternative embodiment, the invention provides a prodrug of a compound of formula (I-I), (I-II), (I-III), (I-IV), (II-I), (II-II), or (II-III), wherein the prodrug comprises a cleavable moiety on the C3 hydroxy as shown in formula (I-I), (I-II), (I-III), (I-IV), (II-I), (II-II), or (II-III).

[0092] “Tautomers” refer to compounds of a particular compound structure in exchangeable forms, and compounds in which the displacement of hydrogen atoms and electrons fluctuates. Thus, the two structures can be in equilibrium by the movement of π electrons and atoms (usually H). For example, enol and ketone are tautomers because they are rapidly interconverted by treatment with either an acid or a base. Another example of tautomerism is the acid and nitro forms of phenylnitromethane, which are similarly formed by treatment with an acid or a base. Tautomers can be relevant to obtaining the optimal chemical reactivity and biological activity of the target compound.

[0093] “Subjects” for which administration is contemplated include humans (i.e., males or females of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults or elderly adults)) and / or non-human animals, such as mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats and / or dogs), but are not limited thereto. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.

[0094] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Examples of oxygen protecting groups include -R aa , -N(R bb )2, -C (=O)SR aa , -C(=O)R aa, -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb )OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3, -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)2N(R bb )2, and -P(=O)(NR bb )2 (where R aa , R bb , and R cc are as defined herein), but are not limited thereto. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3 rd edition, John Wiley & Sons, 1999 (incorporated herein by reference).

[0095] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), benzyl (Bn), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS), t-butylmethoxyphenylsilyl (TBMPS), methanesulfonate (mesylate), and tosylate (Ts).

[0096] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a thiol protecting group). Sulfur protecting groups include -R aa , -N(R bb )2, -C(=O)SR aa, -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb )OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3, -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)2N(R bb )2, and -P(=O)(NR bb )2 are included, but not limited to these, where R aa , R bb , and R cc are as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3 rd edition, John Wiley & Sons, 1999 (incorporated herein by reference).

[0097] In certain embodiments, the substituent present on the nitrogen atom is an amino protecting group (also referred to herein as a nitrogen protecting group). Examples of amino protecting groups include -OH, -OR aa , -N(R cc )2, -C(=O)R aa , -C(=O)OR aa , -C(=O)N(R cc )2, -S(=O)2R aa , -C(=NR cc )R aa , -C(=NR cc )OR aa , -C(=NR cc )N(Rcc ) 2, -SO2N(R cc ) 2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc ) 2, -C(=O)SR cc , -C(=S)SR cc , C 1~10 alkyl, C 2~10 alkenyl, C 2~10 alkynyl, C 3~10 carbocyclic, 3- to 14-membered heterocyclic, C 6~14 aryl, and 5- to 14-membered heteroaryl groups are included, but not limited thereto, where each of alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, where R aa , R bb , R cc , and R dd are as defined herein. Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3 rd rd edition, John Wiley & Sons, 1999 (incorporated herein by reference).

[0098] Exemplary amino protecting groups include amide groups (e.g., -C(=O)R aa )(formamide and acetamide are included, but not limited thereto); carbamate groups (e.g., -C(=O)OR aa )(9-fluorenylmethyl carbamate (Fmoc), t-butyl carbamate (BOC), and benzyl carbamate (Cbz) are included, but not limited thereto); sulfonamide groups (e.g., -S(=O)2R aaExamples include, but are not limited to, p-toluenesulfonamide (Ts), methanesulfonamide (Ms), and N-[2-(trimethylsilyl)ethoxy]methylamine (SEM).

[0099] The terms disease, disorder, and condition are used interchangeably herein.

[0100] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" are intended to mean an action that is performed while a subject is suffering from a particular disease, disorder, or condition and that reduces the severity of, or delays or slows the progression of, the disease, disorder, or condition. In alternative embodiments, the invention contemplates administration of a compound of the invention as a prophylactic agent before a subject begins to suffer from a particular disease, disorder, or condition.

[0101] Generally, an "effective amount" of a compound refers to an amount sufficient to elicit a desired biological response, e.g., sufficient to treat a CNS-related disorder and sufficient to induce anesthesia or sedation. As will be understood by those skilled in the art, the effective amount of a compound of the invention can vary depending on factors such as the desired biological goal, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject. Effective amounts include both therapeutic and prophylactic treatments.

[0102] As used herein, unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent that provides a therapeutic benefit in the treatment of the disease, disorder or condition, either alone or in combination with other therapies. The term "therapeutically effective amount" may include an amount that improves the overall treatment, an amount that reduces or avoids the symptoms or causes of the disease or condition, or an amount that enhances the therapeutic efficacy of another therapeutic agent.

[0103] As used herein, unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or to prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent that provides a prophylactic benefit in the prevention of the disease, disorder or condition, either alone or in combination with other agents. The term "prophylactically effective amount" may include an amount that improves the overall prevention, or an amount that enhances the prophylactic efficacy of another prophylactic agent.

[0104] Compound It should be recognized that the formulas described herein can refer to specific carbon atoms (such as C17, C3, C19, etc.). These references are based on the positions of the carbon atoms according to the steroid nomenclature known and used in the art as shown below:

Chemical formula

[0105] In one aspect, the present specification provides formula (I-I):

Chemical formula

[0106] In one aspect, provided herein are compounds of formula (I-II):

Chemical Formula

[0107] In one aspect, provided herein are compounds of formula (I-III):

Chemical formula

[0108] In one aspect, this specification provides compounds of formula (I-IV): [Chemical formula] or pharmaceutically acceptable salts thereof, where m is 0, 1, or 2; X is -O-, -N(R X ), or -S(O) y -, where R X is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, -S(O)2(R A0 ), -C(O)(R A0 ), or substituted or unsubstituted heteroaryl, where in each case R A0is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and y is 0, 1, or 2; R 3a is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 5 is hydrogen or methyl; R 6a and each of R 6b is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or R 6a and R 6b are joined to form an oxo (=O) group; R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2, -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2R A2, -OS(=O)2OR A1 , -S-S(=O)2R A2 , -S-S(=O)2OR A1 , -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 wherein, in each case, R A1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when bonded to an oxygen atom, a sulfur protecting group when bonded to a sulfur atom, a nitrogen protecting group when bonded to a nitrogen atom, or two R A1 groups are bonded to form a substituted or unsubstituted heterocyclic ring or heteroaryl ring; R A2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 15a R 15b R 16a and R 16b each are independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2, -CN(R A1 )2, -C(O)R A1 , -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 , -SC(=O)SR A1, -SC(=O)N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2R A2 , -OS(=O)2OR A1 , -S-S(=O)2R A2 , -S-S(=O)2OR A1 , -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 wherein, in each case, R A1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when bonded to an oxygen atom, a sulfur protecting group when bonded to a sulfur atom, a nitrogen protecting group when bonded to a nitrogen atom, -SO2R A2 , -C(O)R A2 or two R A1 groups are bonded to form a substituted or unsubstituted heterocyclic ring or heteroaryl ring; R A2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 15a and R 15b or R 16a and R 16b are bonded to form an oxo (=O) group, and R 1a , R 1b , R 2a , R 2b , R 4a , R 4b , R 11a , R 11b , R 12a , and R 12bEach of them is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 wherein R in each case D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when bonded to an oxygen atom, a nitrogen protecting group when bonded to a nitrogen atom, or two R D1 groups are bonded to form a substituted or unsubstituted heterocyclic ring; or R 2a and R 2b , R 4a and R 4b , R 11a and R 11b , and R 12a and R 12b in any one of them are bonded to form an oxo(=O) group.

[0109] For formulas (I-I), (I-II), (I-III), and (I-IV): integer m In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 1 or 2.

[0110] For formulas (I-I), (I-II), (I-III), and (I-IV): X In some embodiments, X is -O-, -N(R X )-, or -S(O) y - wherein R Xis hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, -S(O)2(R A0 ), -C(O)(R A0 ), or substituted or unsubstituted heteroaryl, where in each case R A0 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and y is 0, 1, or 2.

[0111] In some embodiments, X is O.

[0112] In some embodiments, X is -N(R X )-, where R X is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, -S(O)2(R A0 ), -C(O)(R A0 ), or substituted or unsubstituted heteroaryl.

[0113] In some embodiments, X is -N(R X )-, where R X is hydrogen or substituted or unsubstituted alkyl.

[0114] In some embodiments, X is -S(O) y -, and y is 0, 1, or 2. In some embodiments, X is -S(O) y -, and y is 0. In some embodiments, X is -S(O) y -, and y is 1. In some embodiments, X is -S(O) y -, and y is 2.

[0115] Formulas (I-I), (I-II), (I-III), and (I-IV): R 1a and R 1b group In some aspects, R 1a and R 1b are each independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 wherein in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0116] In some aspects, R 1a and R 1b are each independently hydrogen, halogen, cyano, hy droxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2 wherein in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyc ril, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0117] In some aspects, R 1a and R 1b are each independently hydrogen, substituted or unsubstituted alkyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NRD1 C(=O)R D1 wherein, in each case, R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0118] In some aspects, R 1a and R 1b are both hydrogen.

[0119] In some embodiments, R 1a and R 1b are each independently hydrogen or substituted or unsubstituted alkyl.

[0120] In some embodiments, R 1a and R 1b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxy halo, or -OH.

[0121] In some embodiments, R 1a and R 1b are -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0122] Formulas (I-I), (I-II), (I-III), and (I-IV): R 2a and R 2b groups In some aspects, R 2a and R 2b are each independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclic, or substituted or unsubstituted alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 wherein, in each case, R D1is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0123] In some aspects, R 2a and R 2b are each independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2, where in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0124] In some aspects, R 2a and R 2b are each independently hydrogen, substituted or unsubstituted alkyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 , where in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0125] In some aspects, 2a both R 2b and R are hydrogen.

[0126] In some embodiments, R 2a and R 2b are each independently hydrogen or substituted or unsubstituted alkyl.

[0127] In some embodiments, R 2a and R 2b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxy halo, or -OH.

[0128] In some embodiments, R 2a and R 2b are -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0129] Formulas (I-I), (I-II), (I-III), and (I-IV): R 4a and R 4b groups In some aspects, R 4a and R 4b are each independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 , where in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0130] In some aspects, R 4a and R 4b are each independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2, where in each case R D1is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0131] In some aspects, R 4a and R 4b are each independently hydrogen, substituted or unsubstituted alkyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 , where in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0132] In some aspects, both R 4a and R 4b are hydrogen. In further embodiments, R 16a and R 16b are each independently hydrogen or substituted or unsubstituted alkyl.

[0133] In some aspects, R 4a and R 4b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxy halo, or -OH. In some other aspects, R 4a and R 4b are -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0134] Formulas (I-I), (I-II), (I-III), and (I-IV): R 11a and R 11b groups In some embodiments, R 11a and R 11bis, independently of each other, hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 wherein, in each case, R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0135] In some further embodiments, R 11a and R 11b are, independently of each other, hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2, wherein, in each case, R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0136] In some aspects, R 11a and R 11b are, independently of each other, hydrogen, substituted or unsubstituted alkyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 wherein, in each case, R D1is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some aspects, R 11a and R 11b are both hydrogen.

[0137] In some aspects, R 11a and R 11b are each independently hydrogen or substituted or unsubstituted alkyl. In some aspects, R 11a and R 11b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxy halo, or -OH.

[0138] In some aspects, R 11a and R 11b are -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0139] In some embodiments, R 11a and R 11b are joined together to form oxo (=O).

[0140] Formulas (I-I), (I-II), (I-III), and (I-IV): R 15a and R 15b groups In some aspects, R 15a and R 15b are each independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclic, or substituted or unsubstituted alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 , where in each case R D1is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0141] In some embodiments, R 15a and R 15b are each independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2, where in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0142] In some embodiments, R 15a and R 15b are each independently hydrogen, substituted or unsubstituted alkyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 , where in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0143] In some further embodiments, both R 15a and R 15b are hydrogen

[0144] In some aspects, R 15a and R 15b are each independently hydrogen or substituted or unsubstituted alkyl. In some aspects, R 15aand R 15b are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxy halo, or -OH. In some aspects, R 15a and R 15b are -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0145] Formulas (I-I), (I-II), (I-III), and (I-IV): R 16a and R 16b group In some aspects, R 16a and R 16b are each independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 , where in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0146] In some embodiments, R 16a and R 16b are each independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2, where in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0147] In some embodiments, R 16a and R 16b are each independently hydrogen, substituted or unsubstituted alkyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 , where in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0148] In some further embodiments, both R 16a and R 16b are hydrogen

[0149] In some aspects, R 16a and R 16b are each independently hydrogen or substituted or unsubstituted alkyl. In some aspects, R 16a and R 16b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxyhalo, or -OH. In some aspects, R 16a and R 16b are -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0150] Formulas (I-I) and (I-III): R 7a and R 7b groups In some embodiments, R 7a and R 7b are each independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclic, or substituted or unsubstituted alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1)2, or -NR D1 C(=O)R D1 wherein in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R 7a and R 7b combine together to form oxo(=O).

[0151] In some further embodiments, R 7a and R 7b are each independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2, wherein in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0152] In some aspects, R 7a and R 7b are each independently hydrogen, substituted or unsubstituted alkyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 wherein in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0153] In some aspects, R 7a and R 7bAll are hydrogen.

[0154] In some aspects, R 7a and R 7b are each independently hydrogen or substituted or unsubstituted alkyl. In some aspects, R 7a and R 7b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxy halo, or -OH.

[0155] In some aspects, R 7a and R 7b are -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0156] In some embodiments, one of R 7a and R 7b is bonded together to form oxo (=O).

[0157] Formulas (I-I), (I-II), (I-III), and (I-IV): R 5 group In some aspects, R 5 is hydrogen cis to the C19 position. In some other aspects, R 5 is hydrogen trans to the C19 position. In some embodiments, R 5 is methyl cis to the C19 position. In some further embodiments, R 5 is methyl trans to the C19 position.

[0158] Formulas (I-I), (I-II), (I-III), and (I-IV): R 3a group In some embodiments, R 3a is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

[0159] In some embodiments, R 3ais a substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0160] In some embodiments, R 3a is a substituted or unsubstituted alkyl.

[0161] In some embodiments, R 3a is hydrogen. In some embodiments, R 3a is a substituted alkyl (e.g., -CH2OMe or -CH2OEt, etc.). In some embodiments, R 3a is an unsubstituted alkyl. In some embodiments, R 3a is methyl.

[0162] For formulas (I-I) and (I-II): R 19 group In some aspects, R 19 is C1-C6 alkyl. In some aspects, R 19 is deuterium-substituted C1-C6 alkyl.

[0163] In some embodiments, R 19 is a substituted C1-C6 alkyl. In some embodiments, R 19 is an unsubstituted C2-C6 alkyl.

[0164] In some embodiments, R 19 is a substituted C2-C6 alkenyl. In some embodiments, R 19 is an unsubstituted C2-C6 alkenyl.

[0165] In some embodiments, R 19 is a substituted C2-C6 alkynyl. In some embodiments, R 19 is an unsubstituted C2-C6 alkynyl.

[0166] In some aspects, R 19 is ethyl.

[0167] In some embodiments, R 19 is hydrogen.

[0168] Formulas (I-II) and (I-IV): R 6a group and R 6b group

[0169] In some embodiments, R 6a and R 6b are independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

[0170] In some aspects, R 6a and R 6b are independently hydrogen or substituted or unsubstituted alkyl.

[0171] In some aspects, R 6a and R 6b are independently hydrogen or substituted alkyl. In some embodiments, R 6a and R 6b are independently hydrogen or unsubstituted alkyl.

[0172] In some aspects, both 6a R and 6b R are hydrogen. In some aspects, 6a R is halo or alkyl, and 6b R is hydrogen. In some embodiments, both 6a R and 6b R are halo.

[0173] In some aspects, both 6a R and 6b R are alkyl.

[0174] In some embodiments, 6a R and 6b R are joined to form an oxo group.

[0175] Formulas (I-I), (I-II), (I-III), and (I-IV): R12a and R 12b group In some embodiments, R 12a and R 12b are each independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 , where in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0176] In some aspects, R 12a and R 12b are each independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2, where in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0177] In some embodiments, R 12a and R 12b are each independently hydrogen, substituted or unsubstituted alkyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 , where in each case R D1is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0178] In some embodiments, R 12a and R 12b are both hydrogen.

[0179] In some further embodiments, R 12a and R 12b are each independently hydrogen or substituted or unsubstituted alkyl.

[0180] In some embodiments, R 12a and R 12b are joined together to form an oxo group (=O).

[0181] In some embodiments, n is 1. In some other embodiments, n is 2.

[0182] The formulas (I-I), (I-II), (I-III), and (I-IV): R 1 group In some embodiments, R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

[0183] In some embodiments, R 1 is

Chemical formula

[0184] In some embodiments, R 1 is [Chemical formula] and where R in each case 20 is independently halogen, -NO2, -CN, -OR GA , -N(R GA )2, -C(=O)R GA , -C(=O)OR GA , -OC(=O)R GA , -OC(=O)OR GA , -C(=O)N(R GA )2, -N(R GA )C(=O)R GA , -OC(=O)N(R GA )2, -N(R GA )C(=O)OR GA , -S(=O)2R GA , -S(=O)2OR GA , -OS(=O)2R GA , -S(=O)2N(R GA )2, or -N(R GA )S(=O)2R GA ; substituted or unsubstituted C 1~6 alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 alkynyl, substituted or unsubstituted C 3~4 carbocyclyl, substituted or unsubstituted 3- to 4-membered heterocyclyl, or optionally two R GA together with the intervening atom form a substituted or unsubstituted 3- to 4-membered carbocyclic or heterocyclic ring; where R in each case GA is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C 2~6 alkynyl, substituted or unsubstituted C 3~6 carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, or two R GA groups together with the intervening atom form a substituted or unsubstituted carbocyclic or heterocyclic ring; e is 0, 1, 2, or 3, and n is 0, 1, 2, 3, or 4.

[0185] In some embodiments, the compound is of formula (I-Iea) or formula (I-Iea-1)

Chemical formula

[0186] In some embodiments, the compound is of formula (I-Ieg) or formula (I-Ieg-1)

Chemical formula

[0187] In some embodiments, the compound is a compound of formula (I-Ih) or formula (I-Ih-1)

Chemical formula

[0188] In some embodiments, the compound is a compound of formula (I-Ii) or formula (I-Ii-1)

Chemical formula

[0189] In some embodiments, as used herein, formula (II-I):

Chemical formula

Chemical formula

Chemical formula

[0190] In some embodiments, provided herein is a compound of formula (II-II):

Chemical formula

[0191] In some embodiments, herein, formula (II-IIa):

Chemical formula

[0192] In some embodiments, herein, formula (II-III): [Chemical formula] a compound of or a pharmaceutically acceptable salt thereof is provided, where the variables n, R 5 , R 19 , R 1 , R 1a , R 1b , R 2a , R 2b , R 3a , R 4a , R 4b , R 6a , R 6b , R 7a , R 7b , R 11a , R11b , R 12a , R 12b , R 15a , and R 15b are defined as in the case of formula II-I; X b and X b1 each independently is -C(R 15a )(R 15b )-, -O-, -N-, -N(R A1 )-, -S-, -S(O)-, or -S(O)2-, where R A1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, where at least one X b or X b1 is -O-, -N(R A1 )-, -S-, -S(O)-, or -S(O)2-.

[0193] Formula (II-I), (II-II), or (II-III): X a , X b , X b1 , or X c In some embodiments, each of X c independently is -C(R 15a )(R 15b )-, -O-, -N(R B1 )-, -S-, -S(O)-, or -S(O)2-, where R B1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, where one X c is -O-, -N(R A1 )-, -S-, -S(O)-, or -S(O)2-.

[0194] In some embodiments, X aEach of which is independently, -C(R 15a )(R 15b )-, -O-, -N(R A1 )-, -N-, -S-, -S(O)-, or -S(O)2-, where R A1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, where at least one X a is -O-, -N(R A1 )-, -S-, -S(O)-, or -S(O)2-; where at least one X a is -O-, R 3a is hydrogen, R 19 is methyl, and when R 7a or R 7b is hydroxyl, R 15a and R 15b do not form oxo.

[0195] In some embodiments, each of X b and X b1 is independently, -C(R 15a )(R 15b )-, -O-, -N-, -N(R A1 )-, -S-, -S(O)-, or -S(O)2-, where R A1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, where at least one X b or X b1 is -O-, -N(R A1 )-, -S-, -S(O)-, or -S(O)2-.

[0196] In some embodiments, when X b1 is -O- and R 19 is methyl, R 3ais a substituted or unsubstituted alkyl.

[0197] In some embodiments, X c is -O-, -N(H)-, -N(CH3)-, or -N(CH2CH3)-.

[0198] In some embodiments, X b or X b1 is -O-, -N(H)-, -N(CH3)-, or -N(CH2CH3)-.

[0199] In some embodiments, X a is -O-, -N(H)-, -N(CH3)-, -N(CH2CH3)-, or -S(O)2-.

[0200] In some embodiments, X c is -O-.

[0201] Formulas (II-I), (II-II) and (II-III): R 1a and R 1b groups In some aspects, R 1a and R 1b are each independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 wherein in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0202] In some aspects, R 1a and R 1bis, independently of each other, hydrogen, halogen, cyano, hy droxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2, where in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0203] In some aspects, R 1a and R 1b are, independently of each other, hydrogen, substituted or unsubstituted alkyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 , where in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0204] In some aspects, both R 1a and R 1b are hydrogen.

[0205] In some embodiments, R 1a and R 1b are, independently of each other, hydrogen or substituted or unsubstituted alkyl.

[0206] In some embodiments, R 1a and R 1b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxyhalo, or -OH.

[0207] In some embodiments, R 1a and R1b is -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0208] Formulas (II-I), (II-II) and (II-III): R 2a and R 2b group In some embodiments, R 2a and R 2b are each independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 , where in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0209] In some embodiments, R 2a and R 2b are each independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2, where in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0210] In some embodiments, R 2a and R 2b are each independently hydrogen, substituted or unsubstituted alkyl, -OR D1 , -OC(=O)RD1 、 -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 , where in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0211] In some aspects, both R 2a and R 2b are hydrogen.

[0212] In some embodiments, R 2a and R 2b are each independently hydrogen or substituted or unsubstituted alkyl.

[0213] In some embodiments, R 2a and R 2b are independently hydrogen, C1 - C6 alkyl, C1 - C6 haloalkyl, C1 - C6 alkoxy, C1 - C6 alkoxyhalo, or -OH.

[0214] In some embodiments, R 2a and R 2b are -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0215] Formulas (II-I), (II-II) and (II-III): R 4a and R 4b groups In some aspects, R 4a and R 4b are each independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclic, or substituted or unsubstituted alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)RD1 and in each case, R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic ring, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0216] In some aspects, R 4a and R 4b are each independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2, where in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic ring, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0217] In some aspects, R 4a and R 4b are each independently hydrogen, substituted or unsubstituted alkyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 , where in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic ring, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0218] In some aspects, both R 4a and R 4b are hydrogen. In further embodiments, R 16a and R 16b are each independently hydrogen or substituted or unsubstituted alkyl.

[0219] In some aspects, R 4a and R 4b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxy halo, or -OH. In some other aspects, R 4a and R 4b are -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0220] Formulas (II-I), (II-II) and (II-III): R 11a and R 11b groups In some embodiments, R 11a and R 11b are each independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 , where in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0221] In some further embodiments, R 11a and R 11b are each independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2, where in each case R D1is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0222] In some aspects, R 11a and R 11b are each independently hydrogen, substituted or unsubstituted alkyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 , where in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some aspects, both R 11a and R 11b are hydrogen.

[0223] In some aspects, R 11a and R 11b are each independently hydrogen or substituted or unsubstituted alkyl. In some aspects, R 11a and R 11b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxyhalo, or -OH.

[0224] In some aspects, R 11a and R 11b are -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0225] In some embodiments, R 11a and R 11b are joined together to form oxo (=O).

[0226] Formulas (II-I), (II-II) and (II-III): R 15a and R15b Base In some aspects, R 15a and R 15b are each independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 , where in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0227] In some embodiments, R 15a and R 15b are each independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2, where in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0228] In some embodiments, R 15a and R 15b are each independently hydrogen, substituted or unsubstituted alkyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 , where in each case R D1is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0229] In some further embodiments, R 15a and R 15b are both hydrogen.

[0230] In some aspects, R 15a and R 15b are each independently hydrogen or substituted or unsubstituted alkyl. In some aspects, R 15a and R 15b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxyhalo, or -OH. In some aspects, R 15a and R 15b are -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0231] Formulas (II-I), (II-II) and (II-III): R 7a and R 7b groups In some embodiments, R 7a and R 7b are each independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 , where in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocy ryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R7a and R 7b One of them combines to form oxo (=O).

[0232] In some further embodiments, R 7a and R 7b are each independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2, where in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0233] In some aspects, R 7a and R 7b are each independently hydrogen, substituted or unsubstituted alkyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 , where in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0234] In some aspects, all of R 7a and R 7b are hydrogen.

[0235] In some aspects, R 7a and R 7b are each independently hydrogen or substituted or unsubstituted alkyl. In some aspects, R 7a and R 7bis independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxy halo, or -OH.

[0236] In some aspects, R 7a and R 7b are -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0237] In some embodiments, R 7a and R 7b are joined together to form oxo (=O).

[0238] Formulas (II-I), (II-II) and (II-III): R 5 group In some aspects, R 5 is hydrogen that is cis to the C19 position. In some other aspects, R 5 is hydrogen that is trans to the C19 position. In some embodiments, R 5 is methyl that is cis to the C19 position. In some further embodiments, R 5 is methyl that is trans to the C19 position.

[0239] Formulas (II-I), (II-II) and (II-III): R 3a group In some embodiments, R 3a is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

[0240] In some embodiments, R 3a is substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0241] In some embodiments, R 3a is substituted or unsubstituted alkyl.

[0242] In some embodiments, R 3a is hydrogen. In some embodiments, R 3a is substituted alkyl (e.g., -CH2OMe or -CH2OEt, etc.). In some embodiments, R 3a is unsubstituted alkyl. In some embodiments, R 3a is methyl.

[0243] Formulas (II-I), (II-II) and (II-III): R 19 group In some embodiments, R 19 is hydrogen.

[0244] In some aspects, R 19 is C1-C6 alkyl. In some aspects, R 19 is deuterium-substituted C1-C6 alkyl.

[0245] In some embodiments, R 19 is substituted C1-C6 alkyl. In some embodiments, R 19 is unsubstituted C1-C6 alkyl.

[0246] In some embodiments, R 19 is substituted C2-C6 alkenyl. In some embodiments, R 19 is unsubstituted C2-C6 alkenyl.

[0247] In some embodiments, R 19 is substituted C2-C6 alkynyl. In some embodiments, R 19 is unsubstituted C2-C6 alkynyl.

[0248] In some embodiments, R 19 is methyl (e.g., -CH3).

[0249] In some aspects, R 19 is ethyl.

[0250] Formulas (II-I), (II-II), and (II-III): R 6a group and R 6b group In some embodiments, R 6a and R 6b are independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

[0251] In some aspects, R 6a and R 6b are independently hydrogen or substituted or unsubstituted alkyl.

[0252] In some aspects, R 6a and R 6b are independently hydrogen or substituted alkyl. In some embodiments, R 6a and R 6b are independently hydrogen or unsubstituted alkyl.

[0253] In some aspects, both R 6a and R 6b are hydrogen. In some aspects, R 6a is halo or alkyl, and R 6b is hydrogen. In some embodiments, both R 6a and R 6b are halo.

[0254] In some aspects, both R 6a and R 6b are alkyl.

[0255] In some embodiments, R 6a and R 6b combine to form an oxo group.

[0256] Formulas (II-I), (II-II), and (II-III): R 12a and R 12b group In some embodiments, R 12a and R 12bis, independently of each other, hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 wherein in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0257] In some aspects, R 12a and R 12b are, independently of each other, hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, -OR D1 , -OC(=O)R D1 , -NH2, or -N(R D1 )2, wherein in each case R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0258] In some embodiments, R 12a and R 12b are, independently of each other, hydrogen, substituted or unsubstituted alkyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 wherein in each case R D1is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0259] In some embodiments, R 12a and R 12b are both hydrogen.

[0260] In some further embodiments, R 12a and R 12b are each independently hydrogen or substituted or unsubstituted alkyl.

[0261] In some embodiments, R 12a and R 12b are joined together to form an oxo group (=O).

[0262] For formulas (II-I), (II-II) and (II-III): integer n In some embodiments, n is 1. In some other embodiments, n is 2.

[0263] For formulas (II-I), (II-II) and (II-III): R 1 group In some embodiments, R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

[0264] In some embodiments, R 1 is

Chemical formula

Chemical formula

Chemical formula

[0265] In some embodiments, the compound of formula (II-I) is a compound of formula (II-Iba), (II-Ibb), (II-Ibc), or (II-Ibd)

Chemical formula

[0266] In some embodiments, the compound of formula (II-I) is a compound of formula (II-Ica), (II-Icb), (II-Icc), or (II-Icd)

Chemical formula

[0267] In some embodiments, the compound of formula (II-I) is a compound of formula (II-Iea), (II-Ieb), (II-Iec), or (II-Ied)

Chemical formula

[0268] In some embodiments, the compound is of formula (II-Iega), (II-Iegb), (II-Iegc), or (II-Iegd)

Chemical formula

[0269] In some embodiments, the compound of formula (II-I) is a compound of formula (II-Iha), (II-Ihb), (II-Ihc), or (II-Ihd)

Chemical formula

[0270] In some embodiments, the compound of formula (II-II) is a compound of formula (II-IIa), (II-IIaa), (II-IIab), (II-IIac), (II-IIad), or (II-IIae) [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0271] In some embodiments, the compound of formula (II-II) is a compound of formula (II-IIna), (II-IInb), (II-IInc), (II-IInd), or (II-IIne)

Chemical formula

Chemical formula

[0272] In some embodiments, the compound of formula (II-II) is a compound of formula (II-IIma), (II-IImb), (II-IImc), (II-IImd), (II-IIme), (II-IImf), (II-IImg), (II-IImh), (II-IImi), or (II-IImj)

Chemical formula

[0273] In some embodiments, the compound of formula (II-II) is a compound of formula (II-IIpa), (II-IIpb), (II-IIpc), (II-IIpd), (II-IIpe), (II-IIpf), (II-IIpg), (II-IIph), (II-IIpi), (II- IIpj), or (II-IIpk)

Chemical formula

Chemical formula

[0274] In some embodiments, the compound of formula (II-II) is a compound of formula (II-IIwa), (II-IIwb), (II-IIwc), (II-IIwd), (II-IIwe), (II-IIwf), (II-IIwg), (II-IIwh), (II-IIwi), (II-IIwj), or (II-IIwk) [Chemical formula] [Chemical formula] a compound of formula (II-II) or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, or 3; p is 0, 1, 2, or 3; R 32 each of which is independently halogen, alkyl, hydroxyl, or cyano.

[0275] In some embodiments, the compound of formula (II-II) is of formula (II-IIega), (II-IIegb), (II-IIegc), (II-IIegd), (II-IIege) , (II-IIegf), (II-IIegg), (II-IIegh), (II-IIegi), (II-IIegj) or ((II-IIegk)) [Chemical formula] [Chemical formula] a compound of formula (II-II) or a pharmaceutically acceptable salt thereof, wherein u is 0, 1, or 2; each of X is independently -C(R N )-, -C(R N )2-, -O-, -S-, -N-, or N(R N )-, where R N is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, C(=O)R GA , -C(=O)OR GA , -C(=O)N(R GA )2, -S(=O)2R GA , or -S(=O)2N(R GA )2; each R GA is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, substituted or unsubstituted C 2~6 alkenyl, substituted or unsubstituted C2~6 alkynyl, substituted or unsubstituted C 3~6 carbocyclic, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, or two R GA groups together with an intervening atom form a substituted or unsubstituted heterocyclyl or heteroaryl ring.

[0276] In one aspect, provided herein are pharmaceutically acceptable salts of the compounds described herein (e.g., compounds of formula (I-I), (I-II), (I-III), (I-IV), (II-I), (II-II), or (II-III)).

[0277] In one aspect, provided herein are pharmaceutical compositions comprising a compound described herein (e.g., a compound of formula (I-I), (I-II), (I-III), (I-IV), (II-I), (II-II), or (II-III)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the compounds of the invention are provided in the pharmaceutical composition in an effective amount. In certain embodiments, the compounds of the invention are provided in a therapeutically effective amount. In certain embodiments, the compounds of the invention are provided in a prophylactically effective amount.

[0278] The compounds of the invention described herein, in certain embodiments, act, for example, as positive or negative modulators of GABA A receptors. Such compounds are expected to have CNS activity as modulators of the excitability of the central nervous system (CNS) as mediated by their ability to modulate GAB A A receptors. A The compounds of the invention described herein, in certain embodiments, act, for example, as positive or negative modulators of GABA

[0279] Accordingly, in another aspect, there is provided a method for treating a CNS-related disorder in a subject in need of treatment for a CNS-related disorder, the method comprising the step of administering to the subject an effective amount of a compound of the present invention. In certain embodiments, the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a seizure disorder, a memory and / or cognitive disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disorder, a substance use disorder and / or withdrawal syndrome, tinnitus, or status epilepticus. In certain embodiments, the CNS-related disorder is depression. In certain embodiments, the CNS-related disorder is postpartum depression. In certain embodiments, the CNS-related disorder is a major depressive disorder. In certain embodiments, the major depressive disorder is a moderate major depressive disorder. In certain embodiments, the major depressive disorder is a severe major depressive disorder. In certain embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered orally. In certain embodiments, the compound is administered chronically. In certain embodiments, the compound is administered persistently, for example, by continuous intravenous infusion.

[0280] Exemplary compounds of the present invention can be synthesized from the following known starting materials using methods known to those of skill in the art or certain references. In one aspect, provided herein are pharmaceutically acceptable salts of the compounds described herein (e.g., compounds of formula (I-I), (I-II), (I-III), (I-IV), (II-I), (II-II), or (II-III)).

[0281] Alternative embodiments In alternative embodiments, the compounds described herein may also contain one or more isotope substitutions. For example, hydrogen may be, for example, 2 H (D or deuterium) or 3 H (T or tritium); carbon may be, for example, 13 C or 14 C; oxygen may be, for example, 18It may be O; nitrogen may be, for example, 15 It may be N, and so on. In other embodiments, a particular isotope (e.g., 3 H, 13 C, 14 C, 18 O or 15 N) may correspond to at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or at least 99.9% of the total isotope abundance of the element occupying a particular site of the compound. Pharmaceutical composition

[0282] In one aspect, provided herein is a pharmaceutical composition comprising a compound described herein (e.g., a compound of formula (I-I), (I-II ), (I-III), (I-IV), (II-I), (II-II), or (II-III)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the compounds of the invention are provided in an effective amount in the pharmaceutical composition. In certain embodiments, the compounds of the invention are provided in a therapeutically effective amount. In certain embodiments, the compounds of the invention are provided in a prophylactically effective amount.

[0283] In certain embodiments, the pharmaceutical composition comprises an effective amount of an active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of an active ingredient. In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of an active ingredient.

[0284] The pharmaceutical compositions provided herein can be administered by various routes (including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration).

[0285] Generally, the compounds provided herein are administered in an effective amount. The amount of the compound actually administered is typically determined by a physician in light of the relevant circumstances, including the condition being treated, the route of administration selected, the actual compound being administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

[0286] When used to prevent the occurrence of CNS disorders, the compounds provided herein can typically be administered at the dosage levels described above to subjects at risk of developing the condition, by and under the advice of a physician. Subjects at risk of developing a particular condition generally include subjects having a family history of the condition, or subjects identified by genetic testing or screening as being particularly susceptible to the development of the condition.

[0287] The pharmaceutical compositions provided herein are also administered for an extended period of time ( "extended administration"). Extended administration refers to the administration of a compound or its pharmaceutical composition over a long period of time, for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or indefinitely over the remaining period of the subject's life. In certain embodiments, extended administration is intended to provide a constant level of the compound, for example, within the therapeutic window, in the blood over a long period of time.

[0288] The pharmaceutical composition of the present invention can also be delivered using various dosing methods.For example, in certain embodiments, the pharmaceutical composition can be given as a bolus, for example, for the purpose of raising the concentration of the compound in the blood to an effective level. The placement of the bolus dose depends on the systemic level of the active ingredient desired throughout the body, for example, an intramuscular or subcutaneous bolus dose allows for a slow release of the active ingredient, while a bolus delivered directly into a vein (for example, by IV infusion) allows for a faster delivery, which quickly raises the concentration of the active ingredient in the blood to an effective level.In other embodiments, the pharmaceutical composition can be administered as a continuous infusion, for example, by IV infusion, to provide the maintenance of a steady-state concentration of the active ingredient in the subject's body.Furthermore, in still other embodiments, the pharmaceutical composition can be administered as a bolus dose initially, followed by a continuous infusion.

[0289] Compositions for oral administration may take the form of a bulk liquid solution or suspension or a bulk powder. More commonly, however, the compositions are provided in unit dosage form to facilitate accurate dosing. The term "unit dosage form" refers to a unit dose for human subjects and other mammals. It refers to physically discrete units suitable for a quantity, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect together with suitable pharmaceutical excipients. Typical unit dosage forms include pre-measured, pre-filled ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc., in the case of solid compositions. In such compositions, the compound is usually a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various vehicles or excipients and processing aids that help form the desired dosage form.

[0290] In the case of oral administration, oral administration 1 to 5 times per day, particularly 2 to 4 times, typically 3 times, is a representative regimen. When using these dosing patterns, each dose results in a compound provided herein of about 0.01 to about 20 mg / kg, and preferred doses each result in about 0.1 to about 10 mg / kg, particularly about 1 to about 5 mg / kg.

[0291] Transdermal dosages are generally selected to be similar to or to provide lower blood levels than the levels achieved using injection dosages, and generally range from about 0.01 wt% to about 20 wt%, preferably from about 0.1 wt% to about 20 wt%, preferably from about 0.1 wt% to about 10 wt%, and more preferably from about 0.5 wt% to about 15 wt%.

[0292] Dosage levels for injections range from about 0.1 mg / kg / hour to at least 20 mg / kg / hour, all over about 1 to about 120 hours, particularly 24 to 96 hours. A preloading bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve an appropriate steady state level. The maximum total dose is not expected to exceed about 5 g / day for a 40 - 80 kg human patient.

[0293] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle containing buffering agents, suspending agents and dispensing agents, coloring agents, flavorants, etc. Solid forms may include, for example, any of the following components or compounds of similar nature: binders (e.g., microcrystalline cellulose, tragacanth gum or gelatin); excipients (e.g., starch or lactose), disintegrants (e.g., alginic acid, Primogel or corn starch); lubricants (e.g., magnesium stearate); glidants (e.g., colloidal silicon dioxide); sweeteners (e.g., sucrose or saccharin); or flavorants (e.g., peppermint, methyl salicylate or orange flavor).

[0294] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline or other injectable excipients known in the art. As is conventional, the active compounds in such compositions are typically trace components, often in an amount of about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.

[0295] Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient(s). When formulated as an ointment, the active ingredient is typically admixed with a paraffin ointment base or a water-miscible ointment base. Alternatively, the active ingredient can be formulated as a cream, for example, containing an oil-in-water cream base. Such transdermal formulations are well known in the art and generally contain additional components that enhance the skin penetration or stability of the active ingredient or the formulation. All such known transdermal formulations and components are included within the scope provided herein.

[0296] The compounds provided herein can also be administered by transdermal devices. Thus, transdermal administration can be achieved using a reservoir-type or porous membrane-type or solid matrix-type patch.

[0297] The components described above for orally administrable, injectable, or topically administrable compositions are merely representative. Other materials as well as processing techniques, etc., are shown in Remington’s Pharmaceutical Sciences, 17th Edition, 1985, Mack Publishing Company, Easton, Pennsylvania, Part 8 (incorporated herein by reference).

[0298] The compounds of the present invention can also be administered in sustained release form or from a sustained release drug delivery system. Descriptions of representative sustained release materials can be found in Remington’s Pharmaceutical Sciences.

[0299] The present invention also relates to pharmaceutically acceptable acid addition salts of the compounds of the present invention. Acids that can be used to prepare pharmaceutically acceptable salts are non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions (e.g., hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, etc.).

[0300] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient (e.g., a composition suitable for injection such as intravenous (IV) administration).

[0301] Pharmaceutically acceptable excipients include any and all diluents or other liquid vehicles, dispersing or suspending aids, surfactants, isotonic agents, preservatives, lubricants, etc. appropriate for the desired specific dosage form, e.g., suitable for injection. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington’s Pharmaceutical Sciences, 16th edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21st edition (Lippincott Williams & Wilkins, 2005).

[0302] For example, injectable preparations, such as sterile aqueous suspensions for injection, can be formulated by known techniques using suitable dispersing or wetting agents and suspending agents. Exemplary excipients that can be used include, but are not limited to, water, sterile physiological saline or phosphate buffered saline, or Ringer's solution.

[0303] In certain embodiments, the pharmaceutical composition further comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β- and γ-cyclodextrins, each consisting of 6, 7 and 8 α-1,4-linked glucose units, respectively, with one or more substituents as needed on the sugar moieties to be linked, including but not limited to substituted or unsubstituted methylation, hydroxyalkylation, acylation and sulfoalkyl ether substitution. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin also known as CAPTISOL®. See, for example, U.S. Patent No. 5,376,645. In certain embodiments, the composition comprises hexapropyl-β-cyclodextrin. In a more specific embodiment, the composition comprises hexapropyl-β-cyclodextrin (10-50% in water).

[0304] Injectable compositions can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0305] In general, the compounds provided herein are administered in an effective amount. The amount of the compound actually administered will typically be determined by a physician in light of the relevant circumstances, including the condition being treated, the route of administration selected, the actual compound being administered, the age, weight, response of the individual patient, the severity of the patient's symptoms, and the like.

[0306] The composition is provided in unit dosage forms that facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units appropriate as unit doses for human subjects and other mammals, each unit containing a predetermined quantity of the active material calculated to produce the desired therapeutic effect, together with the appropriate pharmaceutical excipients. Typical unit dosage forms include premeasured and prefilled ampules or syringes of liquid compositions. In such compositions, the compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight), the remainder being various vehicles or carriers and processing aids useful in forming the desired dosage form.

[0307] As used herein, "episodic dosing regimen" " is a dosing regimen in which a compound of formula (I-I), (I-II), (I-III), (I-IV), (II-I), (II-II), or (II-III) or a composition comprising a compound of formula (I-I), (I-II), (I-III), (I-IV), (II-I), (II-II), or (II-III) is administered to a subject for a limited period corresponding to the diagnosis of a disorder or its symptoms (e.g., diagnosis or symptoms of depression, major depressive disorder, bipolar depression, anxiety, or postpartum depression episode). In some embodiments, the major depressive disorder is a moderate major depressive disorder. In some embodiments, the major depressive disorder is a severe major depressive disorder. In some embodiments, the compound is formulated as individual dosage units (each unit comprising a compound of formula (I-I), (I-II), (I-III), (I-IV), (II-I), (II-II), or (II-III) and one or more suitable pharmaceutical excipients). In some embodiments, the duration of the dosing regimen at onset is several weeks (e.g., about 8 weeks). In contrast to chronic administration as defined herein, dosing at onset of the compound is carried out for a limited period (e.g., about 2 weeks to about 8 weeks) corresponding to the diagnosis of a disorder (e.g., depression or its symptoms). In some embodiments, dosing at onset is carried out once a day for a plurality of weeks (e.g., about 2 weeks to about 6 weeks). In one embodiment, the duration of dosing at onset is 2 weeks. In some embodiments, more than one dosing regimen at onset (e.g., 2 or more onset regimens) is administered to the subject over the subject's lifetime.

[0308] The compounds provided herein can be administered as a single active agent or in combination with other active agents. In one aspect, the present invention provides a combination of a compound of the present invention and another pharmacologically active agent. Administration in combination can proceed by any technique that is apparent to those skilled in the art (e.g., separate administration, sequential administration, simultaneous administration, and alternating administration).

[0309] The description of the pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, although those skilled in the art will understand that such compositions are generally suitable for administration to all kinds of animals. Modifications for making pharmaceutical compositions suitable for administration to humans into compositions suitable for administration to various animals are well understood, and a veterinary pharmacologist with ordinary knowledge can design and / or carry out such modifications by ordinary experiments. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy The 21st Edition, Lippincott Williams & Wilkins, 2005.

[0310] In one aspect, a kit is provided that includes a composition (e.g., a solid composition) that includes a compound of formula (I-I), (I-II), (I-III), (I-IV), (II-I), (II-II), or (II-III).

[0311] Methods of Use and Treatment In certain aspects, the compounds described herein (e.g., compounds of formula (I-I), (I-II), (I-III), (I-IV), (II-I), (II-II), or (II-III)) are contemplated to be useful as therapeutic agents for treating CNS-related disorders (e.g., sleep disorders, mood disorders (e.g., depression), schizophrenia spectrum disorders, seizure disorders, epilepsy occurrence, memory and / or cognitive impairments, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular disorders, substance use disorders and / or withdrawal syndromes, or tinnitus) in a subject in need thereof (e.g., a subject having Rett syndrome, fragile X syndrome, or Angelman syndrome). Exemplary CNS conditions related to GABA regulation include sleep disorders [e.g., insomnia], mood disorders [e.g., depression (e.g., major depressive disorder (MDD)), mood dysregulation disorder (e.g., mild depression), bipolar disorder (e.g., type I and / or type II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (e.g., obsessive-compulsive disorder (OCD))], schizophrenia spectrum disorders [e.g., schizophrenia, schizoaffective disorder], seizure disorders [e.g., epilepsy (e.g., status epilepticus (SE)), seizures], memory and / or cognitive impairments [e.g., attention disorders (e.g., attention deficit hyperactivity disorder (ADHD)), dementia (e.g., Alzheimer's type dementia, Lewy body type dementia, vascular dementia], movement disorders [e.g., Huntington's disease, Parkinson's disease], personality disorders [e.g., antisocial personality disorder, obsessive-compulsive personality disorder], autism spectrum disorder (ASD) [e.g., autism, single-host causes of autism such as synaptophathy (e.g., Rett syndrome, fragile X syndrome, Angelman syndrome], pain [e.g., neuropathic pain, injury-related pain syndromes, acute pain, chronic pain], traumatic brain injury (TBI), vascular disorders [e.g., stroke, ischemia, vascular malformations], substance use disorders and / or withdrawal syndromes [e.g., addiction to opiates, cocaine, and / or alcohol], and tinnitus, but are not limited thereto.

[0312] In certain embodiments, the CNS-related disorder is a sleep disorder, mood disorder, schizophrenia spectrum disorder, seizure disorder, memory and / or cognitive disorder, movement disorder, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disease, substance use disorder and / or withdrawal syndrome, tinnitus, or status epilepticus. In certain embodiments, the CNS-related disorder is depression. In certain embodiments, the CNS-related disorder is postpartum depression. In certain embodiments, the CNS-related disorder is a major depressive disorder. In certain embodiments, the major depressive disorder is a moderate major depressive disorder. In certain embodiments, the major depressive disorder is a severe major depressive disorder.

[0313] In one aspect, a method of reducing or preventing seizure activity in a subject is provided, the method comprising administering to a subject in need of such treatment an effective amount of a compound of the invention. In some embodiments, the method reduces or prevents the occurrence of seizures.

[0314] In yet another aspect, a combination of a compound of the invention and another pharmacologically active agent is provided. The compounds provided herein can be administered as a single active agent or in combination with other agents. Administration in combination can proceed by any technique apparent to those skilled in the art (e.g., separate administration, sequential administration, simultaneous administration, and alternating administration). can proceed by.

[0315] In another aspect, a method of treating or preventing brain excitability in a subject who is susceptible to or suffering from a condition associated with brain excitability is provided, the method comprising administering to the subject an effective amount of a compound of the invention.

[0316] In yet another aspect, a method of treating or preventing stress or anxiety in a subject is provided, the method comprising administering to a subject in need of such treatment an effective amount of a compound or composition thereof of the invention.

[0317] In yet another aspect, a method for reducing or preventing insomnia in a subject is provided, the method comprising administering to a subject in need of such treatment an effective amount of a compound or composition of the present invention.

[0318] In yet another aspect, a method for inducing sleep and substantially maintaining the level of REM sleep seen in normal sleep, without inducing substantial rebound insomnia, is provided, the method comprising administering an effective amount of a compound of the present invention.

[0319] In yet another aspect, a method for reducing or preventing premenstrual syndrome (PMS) or postnatal depression (PND) in a subject is provided, the method comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention.

[0320] In yet another aspect, a method for treating or preventing mood disorders in a subject is provided, the method comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention. In certain embodiments, the mood disorder is depression.

[0321] In yet another aspect, a method for cognitive enhancement or treatment of memory impairment by administering a therapeutically effective amount of a compound of the present invention to a subject is provided. In certain embodiments, the disorder is Alzheimer's disease. In certain embodiments, the disorder is Rett syndrome.

[0322] In yet another aspect, a method for treating attention disorders by administering a therapeutically effective amount of a compound of the present invention to a subject is provided. In certain embodiments, the attention disorder is ADHD.

[0323] In certain embodiments, the compound is administered to the subject for a long term. In certain embodiments, the compound is administered to the subject orally, subcutaneously, intramuscularly, or intravenously.

[0324] Neuroendocrine disorders and dysfunctions Methods that can be used to treat neuroendocrine disorders and dysfunctions are provided herein. As used herein, "neuroendocrine disorder" or "neuroendocrine dysfunction" refers to various conditions caused by an imbalance in the body's hormone production that is directly related to the brain. Neuroendocrine disorders involve the interaction between the nervous system and the endocrine system. Since the hypothalamus and the pituitary gland are two regions of the brain that control hormone production, damage to the hypothalamus or the pituitary gland, for example due to traumatic brain injury, can affect hormone production and other neuroendocrine functions of the brain. In some embodiments, the neuroendocrine disorder or dysfunction is associated with a female health disorder or condition (e.g., a female health disorder or condition described herein). In some embodiments, the neuroendocrine disorder or dysfunction associated with a female health disorder or condition is polycystic ovary syndrome.

[0325] Symptoms of neuroendocrine disorders include, but are not limited to, behavioral, emotional, and sleep-related symptoms, symptoms related to reproductive function, and physical symptoms, such as fatigue, poor memory, anxiety, depression, weight gain or loss, emotional instability, lack of concentration, difficulty paying attention, loss of libido, infertility, amenorrhea, decrease in muscle mass, increase in abdominal body fat, low blood pressure, low heart rate, hair loss, anemia, constipation, cold intolerance, and dry skin.

[0326] Neurodegenerative diseases and disorders Methods that can be used to treat neurodegenerative diseases and disorders are provided herein. The term "neurodegenerative disease" encompasses diseases and disorders associated with the progressive loss of the structure or function of neurons or neuronal death. Neurodegenerative diseases and disorders include Alzheimer's disease (including symptoms associated with mild, moderate or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic injury; ataxia and spasticity (including for treatment and prevention, and for prevention of seizures caused by schizoid affect disorder or drugs used to treat schizophrenia); benign forgetfulness; cerebral edema; cerebellar ataxia (including McLeod neuroacanthocytosis syndrome (MLS)); closed head injury; coma; injury due to contusion (e.g., spinal cord injury and head injury); dementia (including multi-infarct dementia and senile dementia); disorder of consciousness; Down syndrome; drug-induced or agent-induced parkinsonism (e.g., acute akathisia, acute dystonia, parkinsonism or tardive dyskinesia induced by antipsychotics, neuroleptic malignant syndrome, or agent-induced postural tremor); epilepsy; fragile X syndrome; Gilles de la Tourette syndrome; head injury; hearing impairment and hearing loss; Huntington's disease; Lennox syndrome; dyskinesia induced by levodopa; mental retardation; movement disorders including akinesia and akinetic (rigid) syndromes (including brainstem neurocalcification, corticobasal ganglionic degeneration, multiple system atrophy, parkinsonism-ALS dementia complex, Parkinson's disease, postencephalitic parkinsonism and progressive supranuclear palsy);Disorders associated with muscle contraction and muscle spasticity or weakness (chorea (e.g., benign hereditary chorea, drug-induced chorea, hemiballismus, Huntington's disease, neuroacanthocytosis, Sydenham chorea and symptomatic chorea), dystonia (including tics such as complex tics, simple tics and symptomatic tics), myoclonus (including generalized myoclonus and focal cyloclonus), tremors (e.g., resting tremors, postural tremors and intention tremors) and ataxia (axial ataxia, dystonic writer's cramp, hemiplegic ataxia, episodic ataxia and focal ataxia (e.g., blepharospasm, oromandibular dystonia, as well as spastic dysphonia and torticollis)); neuronal damage (including eye damage, retinopathy or macular degeneration of the eye); stroke, thrombotic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, neurotoxic disorders after perinatal asphyxia and cardiac arrest; Parkinson's disease; seizures; status epilepticus; stroke; tinnitus; tubulosclerosis, as well as neurodegeneration induced by viral infections (e.g., acquired immunodeficiency syndrome (AIDS) and those caused by brain disorders), but not limited to these. Neurodegenerative diseases also include, but are not limited to, stroke, thrombotic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, neurotoxic disorders after perinatal asphyxia and cardiac arrest. Methods for treating or preventing neurodegenerative diseases also include treating or preventing the loss of neuronal function characteristic of neurodegenerative disorders.;

[0327] Mood disorders Mood disorders, such as clinical depression, postpartum depression or postnatal depression, perinatal depression, atypical depression, melancholic depression, psychogenic major depression, catatonic depression, seasonal affective disorder, mood swings, double depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar disorder or manic-depressive disorder, depression caused by chronic conditions, treatment-resistant depression, Methods for treating treatment-resistant depression, suicide, suicidal thoughts or suicidal acts are also provided herein. In some embodiments, the methods described herein provide a therapeutic effect on a subject suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is related to a disease or disorder described herein (e.g., neuroendocrine diseases and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), movement disorders, tremors (e.g., Parkinson's disease), women's health disorders or health conditions).

[0328] Clinical depression, also known as major depression, major depressive disorder (MDD), unipolar depression, unipolar disorder and recurrent depression, refers to a mental disorder characterized by generalized and persistent depressed mood with low self-esteem and usually loss of interest or pleasure in activities that are normally enjoyable. Some people with clinical depression have trouble sleeping, lose weight, generally feel shaky, and become irritable. Clinical depression affects how an individual feels, thinks and behaves, and can lead to a variety of emotional and physical problems. Individuals with clinical depression may have difficulty performing daily activities and may feel as if life is not worth living.

[0329] Perinatal depression refers to depression during pregnancy. Symptoms include irritability, crying, anxiety, sleep difficulties, extreme fatigue (emotional and / or physical), changes in appetite, difficulty concentrating, increased anxiety and / or worry, feelings of wanting to be away from the baby and / or fetus, and loss of interest in activities previously enjoyed.

[0330] Postpartum depression (PND), also referred to as postnatal depression (PPD), refers to a type of clinical depression that affects women after childbirth. Symptoms may include sadness, fatigue, changes in sleep and eating habits, decreased sexual desire, crying episodes, anxiety and irritability. In some embodiments, PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein). In some embodiments, PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein).

[0331] In some embodiments, a subject having PND is also experiencing depression or symptoms of depression during pregnancy. This depression is referred to herein as perinatal depression. In certain embodiments, a subject experiencing perinatal depression is at high risk of experiencing PND.

[0332] Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anhedonia) and positivity, significant weight gain or increased appetite. Patients suffering from AD may also have excessive sleep or drowsiness (hypersomnia), heaviness in the limbs, and significant social impairment as a result of perceived hypersensitivity to interpersonal rejection.

[0333] Melancholic depression is characterized by loss of pleasure in most or all activities (anhedonia), non-responsiveness to pleasurable stimuli, a more pronounced depressive mood than a mood of grief or loss, significant weight loss, or excessive guilt.

[0334] Psychotic major depression (PMD) or psychotic depression refers to a major depressive episode, particularly a melancholic major depressive episode, in which an individual experiences psychotic symptoms such as delusions and hallucinations.

[0335] Catatonic depression refers to a major depressive disorder accompanied by motor behavioral disturbances and other symptoms. An individual may become mute, stuporous, immobile, or exhibit purposeless or strange movements.

[0336] Seasonal affective disorder (SAD) refers to a type of seasonal depression in which an individual has seasonal patterns of depressive episodes that begin in the fall or winter.

[0337] Mood swings refer to conditions associated with unipolar depression, and the same physical and cognitive problems are evident. They tend to be less severe and last longer (e.g., at least 2 years).

[0338] Double depression refers to a state of marked depression (mood swings) that lasts for at least 2 years and is occasionally interrupted by periods of major depression.

[0339] Dysthymic personality disorder (DPD) refers to a personality disorder with depressive characteristics.

[0340] Recurrent Brief Depression (RBD) refers to a state in which an individual has depressive episodes approximately once a month, and each episode lasts for 2 weeks or a shorter period, typically less than 2 - 3 days.

[0341] Minor depressive disorder or minor depression refers to depression in which at least two symptoms are present for 2 weeks.

[0342] Bipolar disorder or manic - depressive disorder causes extreme mood swings that include high (mania or hypomania) and low (depression) moods. During the manic phase, an individual may feel or act abnormally happy, energetic, or irritable. They often make impulsive decisions with little regard for the consequences. Usually, the desire for sleep decreases. During the depressive phase, they may cry, avoid eye contact with others, and have a negative view of life. The risk of suicide for those with this disorder is high, over 6% in 20 years, and 30 - 40% engage in self - harm. Other mental health problems such as anxiety disorders and substance use disorders commonly co - occur with bipolar disorder.

[0343] Depression caused by chronic medical conditions refers to depression caused by chronic medical conditions such as cancer, chronic pain, chemotherapy, chronic stress, etc.

[0344] Treatment-resistant depression refers to a state in which an individual is undergoing treatment for depression but the symptoms do not improve. For example, antidepressants or psychological counseling (psychotherapy) do not alleviate the depressive symptoms of an individual with treatment-resistant depression. In some cases, an individual with treatment-resistant depression may experience symptom improvement but then relapse. Treatment-resistant depression occurs in patients suffering from depression that is resistant to standard pharmacological treatments, including tricyclic antidepressants, MAOIs, SSRIs, and dual and triple uptake inhibitors, and / or anxiolytics, as well as non-pharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation, and / or transcranial magnetic stimulation).

[0345] Postoperative depression refers to a depressive state following a surgical procedure (e.g., as a result of facing death). For example, an individual may experience persistent sadness or emptiness, loss of pleasure or interest in hobbies and activities that were previously enjoyable, or persistent feelings of worthlessness or despair.

[0346] Mood disorders related to a female's health condition or health disorder refer to mood disorders (e.g., depression) that are related to (e.g., caused by) a female's health condition or health disorder (e.g., those described herein).

[0347] Suicidal tendency, suicidal ideation, and suicidal behavior refer to the tendency of an individual to commit suicide. Suicidal ideation is related to thoughts about suicide or an abnormal preoccupation with suicide. The scope of suicidal ideation can vary widely, from momentary thoughts to extensive thoughts, detailed plans, role-playing, and incomplete attempts. Symptoms may include talking about suicide, obtaining means to commit suicide, cutting off social contact, thinking only about death, feeling immobilized or hopeless about a situation, increased use of alcohol or drugs, engaging in risky or self-destructive behavior, and saying goodbye to people as if they will never see them again.

[0348] Symptoms of depression include persistent feelings of anxiety or sadness, feelings of weakness, hopelessness, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, motor challenges, loss of interest in pleasurable activities or hobbies, decreased concentration, decreased energy, low self-esteem, lack of positive thoughts or plans, excessive sleep, overeating, loss of appetite, insomnia, self-harm, thoughts of suicide, and suicide attempts. The presence, severity, frequency, and duration of symptoms can vary from case to case. The symptoms of depression and their alleviation can be confirmed by a physician or psychologist (e.g., a mental status examination).

[0349] In some embodiments, the method includes monitoring a subject using known depression scales, such as the Hamilton Depression (HAM-D) scale, the Clinical Global Impression - Improvement scale (CGI), and the Montgomery - Asberg Depression Rating Scale (MADRS). In some embodiments, the treatment effect can be measured by a decrease in the total Hamilton Depression (HAM-D) score exhibited by the subject. The decrease in the HAM-D total score can occur within 4, 3, 2, or 1 day; or within or less than 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, 8 hours. The treatment effect can be evaluated over a specific treatment period. For example, the treatment effect can be measured by a decrease in the total HAM-D score from baseline after administration of a compound described herein (e.g., a compound of formula (I-I), (I-II), (I-III), (I-IV), (II-I), (II-II), or (II-III)) (e.g., 12, 24, or 48 hours after administration; or after 24, 48, 72, or 96 hours or more; or after 1 day, 2 days, 14 days, 21 days, or 28 days; or after 1 week, 2 weeks, 3 weeks, or 4 weeks; or after 1 month, 2 months, 6 months, or 10 months; or after 1 year, 2 years, or over a lifetime).

[0350] In some embodiments, the subject has a mild depressive disorder, e.g., mild major depressive disorder. In some embodiments, the subject has a moderate depressive disorder, e.g., moderate major depressive disorder. In some embodiments, the subject has a severe depressive disorder, e.g., severe major depressive disorder. In some embodiments, the subject has a very severe depressive disorder, e.g., very severe major depressive disorder. In some embodiments, the baseline HAM-D total score of the subject (i.e., before treatment with a compound described herein (e.g., a compound of formula (I-I), (I-II), (I-III), (I-IV), (II-I), (II-II), or (II-III))) is at least 24. In some embodiments, the baseline HAM-D total score of the subject is at least 18. In some embodiments, the baseline HAM-D total score of the subject is between 14 and 18, including 14 and 18. In some embodiments, the baseline HAM-D total score of the subject is between 19 and 22, including 19 and 22. In some embodiments, the HAM-D total score of the subject before treatment with a compound described herein (e.g., a compound of formula (I-I), (I-II), (I-III), (I-IV), (II-I), (II-II), or (II-III)) is greater than or equal to 23. In some embodiments, the baseline score is at least 10, 15, or 20. In some embodiments, the HAM-D total score of the subject after treatment with a compound described herein (e.g., a compound of formula (I-I), (I-II), (I-III), (I-IV), (II-I), (II-II), or (II-III)) is It is about 0 to 10 (for example, less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2 or 1.8). In some embodiments, the total HAM-D score after treatment with the compounds described herein (for example, the compounds of formula (I-I), (I-II), (I-III), (I-IV), (II-I), (II-II), or (II-III)) is less than 10, 7, 5 or 3. In some embodiments, the decrease in the total HAM-D score is from a baseline score of about 20 to 30 (for example, 22 to 28, 23 to 27, 24 to 27, 25 to 27, 26 to 27) to about 0 to 10 (for example, less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2 or 1.8) of the total HAM-D score after treatment with the compounds described herein (for example, the compounds of formula (I-I), (I-II), (I-III), (I-IV), (II-I), (II-II), or (II-III)). In some embodiments, the decrease from the baseline total HAM-D score to the total HAM-D score after treatment with the compounds described herein (for example, the compounds of formula (I-I), (I-II), (I-III), (I-IV), (II-I), (II-II), or (II-III)) is at least 1, 2, 3, 4, 5, 7, 10, 25, 40, 50 or 100-fold). In some embodiments, the reduction rate from the baseline total HAM-D score to the total HAM-D score after treatment with the compounds described herein (for example, the compounds of formula (I-I), (I-II), (I-III), (I-IV), (II-I), (II-II), or (II-III)) is at least 50% (for example, 60%, 70%, 80% or 90%). In some embodiments, the therapeutic effect is measured as a decrease in the total HAM-D score after treatment with the compounds described herein (for example, the compounds of formula (I-I), (I-II), (I-III), (I-IV), (II-I), (II-II), or (II-III)) (for example, 12, 24, 48 hours after administration; or 24, 48, 72, 96 hours or more after; or 1 day, 2 days, 14 days or more after) compared to the baseline total HAM-D score, and is at least 10, 15 or 20 points.

[0351] In some embodiments, a method of treating a depressive disorder, such as major depressive disorder, provides a treatment effect (e.g., as measured by a decrease in the Hamilton Depression Rating Scale (HAM-D)) within 14, 10, 4, 3, 2, or 1 day or within 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, a method of treating a depressive disorder, such as major depressive disorder, provides a treatment effect (e.g., as determined by a statistically significant decrease in the HAM-D total score) within 1 day or 2 days of treatment with a compound described herein (e.g., a compound of formula (I-I), (I-II), (I-III), (I-IV), (II-I), (II-II), or (II-III)). In some embodiments...

Claims

【Claim 1】Brain excitability.

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